<SEC-DOCUMENT>0000874015-19-000045.txt : 20190301
<SEC-HEADER>0000874015-19-000045.hdr.sgml : 20190301
<ACCEPTANCE-DATETIME>20190301143905
ACCESSION NUMBER:		0000874015-19-000045
CONFORMED SUBMISSION TYPE:	10-K
PUBLIC DOCUMENT COUNT:		121
CONFORMED PERIOD OF REPORT:	20181231
FILED AS OF DATE:		20190301
DATE AS OF CHANGE:		20190301

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:			DE
		FISCAL YEAR END:			1231

	FILING VALUES:
		FORM TYPE:		10-K
		SEC ACT:		1934 Act
		SEC FILE NUMBER:	000-19125
		FILM NUMBER:		19648494

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

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

	FORMER COMPANY:	
		FORMER CONFORMED NAME:	ISIS PHARMACEUTICALS INC
		DATE OF NAME CHANGE:	19930328
</SEC-HEADER>
<DOCUMENT>
<TYPE>10-K
<SEQUENCE>1
<FILENAME>form10k.htm
<DESCRIPTION>IONIS PHARMACEUTICALS INC 10-K 12-31-2018
<TEXT>
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    <div style="text-align: center;"><font style="font-size: 18pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">SECURITIES AND EXCHANGE COMMISSION</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Washington, DC 20549</font></div>
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    <div style="text-align: center;"><font style="font-size: 18pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">FORM 10-K</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> </font><br>
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE
                      SECURITIES EXCHANGE ACT OF 1934</font></font></div>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">For the fiscal year ended December 31, 2018</font></div>
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">TRANSITION</font><font style="font-size: 10pt; font-family:
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    <div style="text-align: left; text-indent: 36pt; margin-left: 14.4pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For the transition period from ___________ to ___________</font></div>
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    <div style="text-align: center;"><font style="font-size: 18pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis Pharmaceuticals, Inc.</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(Exact name of Registrant as specified in its charter)</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Delaware</font></div>
          </td>
          <td style="width: 2.13%; vertical-align: bottom;">&#160;</td>
          <td style="width: 48.88%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">33-0336973</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(State or other jurisdiction of incorporation or organization)</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(IRS Employer Identification No.)</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2855 Gazelle Court, Carlsbad, CA</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(Address of Principal Executive Offices)</font></div>
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          <td style="width: 2%; vertical-align: bottom;">&#160;</td>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">760-931-9200</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(Registrant&#8217;s telephone number, including area code)</font></div>
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    <div style="text-align: center; margin-top: 6pt; margin-bottom: 6pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Securities registered pursuant to Section 12(b) of the Act:</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Name of each exchange on which registered</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Common Stock, $.001 Par Value</font></div>
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          <td style="width: 7.25%; vertical-align: top;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The Nasdaq Stock Market, LLC</font></div>
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    <div style="text-align: left; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
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    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Securities registered pursuant to Section 12(g) of the Act: <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;
          font-weight: bold;">None</font></font></div>
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    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9746;&#160; </font>No <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</font></font></div>
    <div style="text-align: justify; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Indicate by check if the Registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;&#160; </font>No <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9746;</font></font></div>
    <div style="text-align: justify; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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. Yes <font style="font-size: 10pt;
          font-family: 'Segoe UI Symbol';">&#9746;&#160; </font>No <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</font></font></div>
    <div style="text-align: justify; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to
        Rule 405 of Regulation S-T (&#167;232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9746;&#160; </font>No





        <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</font></font></div>
    <div style="text-align: left; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
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    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K is not contained herein, and will not be
        contained, to the best of Registrant&#8217;s knowledge, in definitive proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K. <font style="font-size: 10pt; font-family: 'Segoe UI
          Symbol';">&#9744;</font></font></div>
    <div style="text-align: left; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller
        reporting company, or an emerging growth company. See the definitions of &#8220;large accelerated filer,&#8221; &#8220;accelerated filer,&#8221; &#8220;smaller reporting company,&#8221; and &#8220;emerging growth company&#8221; in Rule 12b-2 of the Exchange Act. (Check one):</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Large accelerated filer <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9746;</font></font></div>
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          <td style="width: 2.13%; vertical-align: bottom;">&#160;</td>
          <td style="width: 48.88%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accelerated filer <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</font></font></div>
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          <td style="width: 49%; vertical-align: top;">&#160;</td>
          <td style="width: 2.13%; vertical-align: bottom;">&#160;</td>
          <td style="width: 48.88%; vertical-align: top;">&#160;</td>
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          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-accelerated filer <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</font></font></div>
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          <td style="width: 2.13%; vertical-align: bottom;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Smaller reporting company <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</font></font></div>
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          <td style="width: 49%; vertical-align: top;">&#160;</td>
          <td style="width: 2.13%; vertical-align: bottom;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Emerging growth company <font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;</font></font></div>
          </td>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
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    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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 7(a)(2)(B) of the Securities Act. </font><font style="font-size: 10pt;
          font-family: 'Segoe UI Symbol';">&#9744;</font></font></div>
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    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Indicate by check mark whether the Registrant is a shell company
          (as defined in Rule 12b-2 of the Act). Yes </font><font style="font-size: 10pt; font-family: 'Segoe UI Symbol';">&#9744;&#160; </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">No </font><font style="font-size: 10pt;
          font-family: 'Segoe UI Symbol';">&#9746;</font></font></div>
    <div style="text-align: left; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
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    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The approximate aggregate market value of the voting common stock held by non-affiliates of the Registrant, based upon the last sale price of
        the common stock reported on The Nasdaq Global Select Market was $4,805,287,142 as of June 30, 2018.*</font></div>
    <div style="text-align: left; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The number of shares of voting common stock outstanding as of February 20, 2019 was 138,397,754.</font></div>
    <div><br>
    </div>
    <div style="text-align: center; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">DOCUMENTS INCORPORATED BY REFERENCE</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Portions of the Registrant&#8217;s definitive Proxy Statement to be filed on or about April 26, 2019 with the Securities and Exchange Commission in
        connection with the Registrant&#8217;s annual meeting of stockholders to be held on June 6, 2019 are incorporated by reference into Part III of this Report.</font></div>
    <div style="text-align: left; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zb5515f577024431dafeb19c70d3db6f4" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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          <td style="width: 31.46%; vertical-align: top; border-bottom: #000000 2px solid;">&#160;</td>
          <td style="width: 68.54%; vertical-align: top;">&#160;</td>
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    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z64ccb8d1f54a474092d7172d326a8bec" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">*</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Excludes 21,838,695 shares of common stock held by directors and officers and by stockholders whose beneficial ownership is known by the Registrant to exceed
                    10 percent of the common stock outstanding at June 30, 2018. Exclusion of shares held by any person should not be construed to indicate that such person possesses the power, direct or indirect, to direct or cause the direction of the
                    management or policies of the Registrant, or that such person is controlled by or under common control with the Registrant.</font></div>
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    <!--PROfilePageNumberReset%Num%2%%%-->
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">FORWARD-LOOKING STATEMENTS</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">This report on Form 10-K and the information incorporated herein by reference includes forward-looking
        statements regarding our business and the therapeutic and commercial potential of SPINRAZA (nusinersen), TEGSEDI (inotersen), WAYLIVRA (volanesorsen) and our technologies and products in development, including the business of Akcea Therapeutics,
        Inc., our majority-owned affiliate. 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, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such
        drugs. Our forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause our results to differ materially from those expressed or implied by such forward-looking statements. Factors that could
        cause or contribute to such differences include, but are not limited to, those discussed in this report on Form 10-K, including those identified in Item 1A entitled &#8220;Risk Factors&#8221;. Although our forward-looking statements reflect the good faith
        judgment of our management, these statements are based only on facts and factors currently known by us. As a result, you are cautioned not to rely on these forward-looking statements.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In this report, unless the context requires otherwise, &#8220;Ionis,&#8221; &#8220;Company,&#8221; &#8220;we,&#8221; &#8220;our,&#8221; and &#8220;us&#8221; refers to Ionis
        Pharmaceuticals, Inc. and its subsidiaries.</font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">TRADEMARKS</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>&#8220;Ionis,&#8221; the Ionis
        logo, and other trademarks or service marks of Ionis Pharmaceuticals,&#160;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,&#160;Inc. appearing
        in this report are the property of Akcea Therapeutics,&#160;Inc. 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">CORPORATE INFORMATION</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We incorporated in California in 1989 and in January 1991 we changed our state of incorporation to Delaware. In December
        2015, we changed our name to Ionis Pharmaceuticals, Inc. from Isis Pharmaceuticals, Inc. Our principal offices are in Carlsbad, California. We make available, free of charge, on our website, <font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif; font-style: italic;">www.ionispharma.com</font>, our reports on Forms 10-K, 10-Q, 8-K and amendments thereto, as soon as reasonably practical after we file such materials with the Securities and Exchange Commission. Any
        information that we include on or link to our website is not a part of this report or any registration statement that incorporates this report by reference. You may also read and copy our filings at the SEC&#8217;s Public Reference Room at 100 F Street,
        NE, Washington, DC 20549. You may obtain information on the operation of the Public Reference Room by calling the SEC at 1-800-732-0330. The SEC also maintains a website that contains reports, proxy and information statements, and other information
        regarding issuers that file electronically with the SEC. The address of that site is <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">www.sec.gov</font>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2014, we formed Akcea Therapeutics, Inc., as a Delaware corporation, with its principal office in Boston,
        Massachusetts. Prior to Akcea&#8217;s IPO in July 2017, we owned 100 percent of Akcea&#8217;s stock. At December 31, 2018, we owned approximately 75 percent of Akcea&#8217;s stock.</font></div>
    <div><br>
    </div>
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      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">2</font></div>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">FORM 10-K</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">For the Fiscal Year Ended December 31, 2018</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Table of Contents</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z7549905267444d31ba15452870657dd7" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 10.55%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">PART I</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top;">&#160;</td>
          <td style="width: 6.22%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top;">&#160;</td>
          <td style="width: 83.23%; vertical-align: top;">&#160;</td>
          <td style="width: 6.22%; vertical-align: top; border-bottom: 2px solid black;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Page</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 1.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Business</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 1A.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Risk Factors</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">39</font></div>
          </td>
        </tr>
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          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 1B.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Unresolved Staff Comments</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 2.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Properties</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 3.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Legal Proceedings</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48</font></div>
          </td>
        </tr>
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          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 4.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Mine Safety Disclosures</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">49</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">PART II</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 5.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Market for Registrant&#8217;s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">49</font></div>
          </td>
        </tr>
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          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 6.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selected Financial Data</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">49</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 7.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Management&#8217;s Discussion and Analysis of Financial Condition and Results of Operations</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 7A.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Quantitative and Qualitative Disclosures About Market Risk</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">75</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 8.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Financial Statements and Supplementary Data</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">75</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 9.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Changes in and Disagreements With Accountants on Accounting and Financial Disclosure</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">75</font></div>
          </td>
        </tr>
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          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 9A.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Controls and Procedures</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">75</font></div>
          </td>
        </tr>
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          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 9B.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other Information</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">77</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">PART III</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 10.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Directors, Executive Officers and Corporate Governance</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">77</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 11.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Executive Compensation</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">77</font></div>
          </td>
        </tr>
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          <td style="width: 10.55%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 12.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">77</font></div>
          </td>
        </tr>
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          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 13.</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Certain Relationships and Related Transactions, and Director Independence</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">77</font></div>
          </td>
        </tr>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 14.</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Principal Accounting Fees and Services</font></div>
          </td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">77</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">PART IV</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
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          <td style="width: 10.55%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 15.</font></div>
          </td>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Exhibits, Financial Statement Schedules</font></div>
          </td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">78</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Signatures</font></div>
          </td>
          <td style="width: 83.23%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 6.22%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
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    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">PART I</div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 1. Business</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are a leader in discovering and developing RNA-targeted therapeutics with sustained and growing revenues. We have
        created an efficient and broadly applicable drug discovery platform leveraging our expertise in antisense oligonucleotide therapeutics that we believe has fundamentally changed medicine and transformed the lives of people with devastating and often
        deadly diseases. Our large, diverse and advanced pipeline of over 40 first-in-class and/or best-in-class medicines addresses diseases across a broad range of therapeutic areas, targeting small, medium and large patient populations.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have two commercial medicines approved in major markets around the world, SPINRAZA and TEGSEDI. We have at least four
        medicines that have entered pivotal studies or have the potential to begin pivotal studies this year, and another six medicines that could start pivotal studies in 2020. These medicines, along with the more than 30 additional medicines in our
        pipeline, represent multiple potential drivers of value for years to come. We believe our efficient drug discovery platform, coupled with our innovation-centric business model, provides us with the flexibility to determine the optimal development
        and commercialization strategy to maximize the commercial opportunity for each of our medicines and ensure that we continue to produce transformative medicines for patients who need them. We believe we are positioned to drive substantial value for
        patients and shareholders.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As of January 2019, SPINRAZA was approved in over 40 countries around the world, and our partner Biogen, who is
        responsible for global SPINRAZA commercial activities, reported that more than 6,600 patients are now on SPINRAZA therapy. In addition, Biogen plans to continue to pursue regulatory filings in additional countries. Biogen reported 2018 annual sales
        of SPINRAZA of more than $1.7 billion, and we earned $238 million in commercial revenues from royalties on sales of SPINRAZA. SPINRAZA is the first and only approved medicine for the treatment of spinal muscular atrophy, or SMA. SPINRAZA is the
        established standard-of-care for all people with this progressive, debilitating and often fatal genetic disease. In November 2018, SPINRAZA was recognized with the 2018 International Prix Galien award as Best Biotechnology Product. This prestigious
        honor marks the seventh Prix Galien award for SPINRAZA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI, a once weekly, self-administered subcutaneous medicine, was approved in 2018 in the U.S., EU and Canada for the
        treatment of polyneuropathy caused by hereditary TTR amyloidosis, or hATTR, in adult patients. hATTR is a debilitating, progressive, and fatal disease. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea, our
          majority-owned affiliate focused on developing and commercializing medicines to treat patients with rare and serious diseases, </font>launched TEGSEDI globally in late 2018. In the fourth quarter of 2018, we earned more than $2 million in
        TEGSEDI product sales. Akcea has an exclusive license agreement with PTC Therapeutics, or PTC, to commercialize TEGSEDI in Latin America. In January 2019, PTC filed an application for regulatory approval in Brazil with ANVISA, the Brazilian
        regulatory authority. ANVISA granted priority review for TEGSEDI.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We and Akcea are preparing to commercialize
          WAYLIVRA in the EU. The Committee for Medicinal Products for Human Use, or CHMP, of the European Medicines Agency, or EMA, adopted a positive opinion recommending conditional marketing authorization for WAYLIVRA as an adjunct to diet in adult
          patients with genetically confirmed familial chylomicronemia syndrome, or FCS, who are at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate. The positive opinion will now be referred to the
          European Commission, or EC, which grants marketing authorization for medicines in the EU, as well as to European Economic Area members Iceland, Liechtenstein and Norway. With this positive opinion, and, pending adoption of the positive opinion by
          the EC, Akcea plans to leverage its existing commercial infrastructure in Europe to market WAYLIVRA. </font>Akcea is continuing to conduct open-label extension and early access programs.<font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;"> We are also focused on regulatory discussions in the U.S. We are developing WAYLIVRA to treat familial partial lipodystrophy, or FPL, a second severe and rare, genetically defined disease. FCS and FPL are orphan diseases
          characterized by severely high triglyceride levels that result in severe, daily symptoms and a high risk of life-threatening pancreatitis.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In addition to commercializing TEGSEDI and preparing to commercialize WAYLIVRA, Akcea is developing four other
        clinical-stage medicines: AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>(TQJ230), AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AKCEA-TTR-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, </font>each of which could potentially treat multiple patient populations. Moving these drugs into Akcea allows us to retain substantial value from these medicines and
        ensures our core focus remains on innovation.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> As of February 2019, we owned approximately 75 percent of Akcea.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are continuously advancing our technology and pipeline to provide the most value to patients. We have a pipeline of
        over 40 medicines that, like SPINRAZA and TEGSEDI, have the potential to transform the treatment of diseases with no adequate treatment today. These medicines range from treatments for rare diseases with small patient populations to more common
        diseases afflicting millions of patients. Our pipeline covers a broad spectrum of therapeutic areas, such as cardiometabolic diseases, neurodegenerative diseases, cancer, severe and rare diseases and others. We believe our large and diverse
        pipeline contains many near-, mid- and longer-term growth drivers for the company.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our pipeline includes at least 10 potentially transformative medicines anticipated to enter pivotal clinical studies in
        the next two years. We anticipate at least four of these medicines will enter pivotal studies this year including: AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, AKCEA-TTR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> (RG6042) and IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. Roche recently
        initiated a Phase 3 study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>for Huntington&#8217;s disease, or HD. We believe each of these medicines is a first-in-class and/or best-in-class medicine with the potential to deliver significant value to patients and shareholders.
        We anticipate that the data from these pivotal studies, if positive, will support global regulatory filings for each medicine.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> (TQJ230) &#8211; </font>In February 2019, Novartis exercised its option to license AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        and we earned a $150 million license fee. Novartis is responsible for conducting and funding all future development and commercialization activities for AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, including a global pivotal cardiovascular outcomes study, for
        which planning and initiation activities are underway. AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> targets a cardiovascular risk factor, lipoprotein(a) or Lp(a). Lp(a) is well-recognized by the medical community as a major risk factor for cardiovascular disease.
        Lp(a) is genetically determined at birth and there are currently no treatments available to substantially and specifically lower Lp(a). In September 2018, we reported dose-dependent and substantial reductions in Lp(a) levels in the Phase 2 clinical
        study in patients with established cardiovascular disease, or CVD, due to elevated levels of Lp(a), which was also the longest and largest study, regardless of phase, conducted with a LICA antisense medicine to date. Approximately 98 percent of
        patients who received the highest dose in the study demonstrated a reduction in Lp(a) levels to below 50 mg/dL, the recognized threshold for risk of CVD. In addition, AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated a favorable safety and tolerability
        profile in the study.</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-TTR-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211; </font>We are developing AKCEA-TTR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for the treatment of people with all forms of TTR
        amyloidosis as a once a month or even less frequent subcutaneous self-administered injection. In April 2018, we licensed to Akcea the worldwide rights to commercialize TEGSEDI and AKCEA-TTR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. We plan to report data from the Phase 1/2
        study this year, followed by the initiation of a pivotal program. We plan to initiate a Phase 3 study in patients with hereditary TTR amyloidosis with polyneuropathy first, followed closely by a Phase 3 study in patients with wild type and
        hereditary TTR cardiomyopathy, also planned for this year.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-HTT</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> (RG6042) &#8211; </font>Roche initiated the Phase 3 study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for HD in December 2018
        and we earned a $35 million milestone payment when the first patient was dosed in the Phase 3 study in January 2019. HD is a genetic, devastating and fatal neurodegenerative disease that negatively affects psychological, cognitive and motor
        functions. In March 2018, we reported data from a Phase 1/2 study that demonstrated up to a 60 percent reduction in the mutant huntingtin protein, or mHTT, as observed in the cerebral spinal fluid, or CSF. It was the first study to demonstrate
        disease-modifying potential in HD patients. Based on preclinical data, the mHTT reductions of 40-60 percent in the CSF are predicted to result in 55-85 percent reduction in the cortex of the brain, where mHTT is highly expressed. IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        demonstrated a favorable safety and tolerability profile in the study.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-SOD1</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> (BIIB067) &#8211; </font>IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, for people with<font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>amyotrophic lateral sclerosis, or ALS, is the fourth medicine we anticipate we will move into pivotal studies this year. ALS is a rare, fatal neurodegenerative disease characterized by
        the loss of motor neurons&#160; in the brain and spinal cord resulting in an inability to control muscle movement.&#160; Scientists have identified mutations within multiple genes as causative of ALS, including mutations in the SOD1 gene. IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        directly targets the SOD1 gene and is delivered intrathecally into the CSF.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>The average life expectancy for an ALS patient with the SOD1 mutation
        is less than five years from the time of diagnosis. Based on the positive interim analysis from the Phase 1/2 study that demonstrated proof-of-biology and proof-of-concept, in December 2018, Biogen exercised its licensing option with us to develop
        and commercialize IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>demonstrated a favorable safety and tolerability profile in the study. Biogen plans to add an additional cohort to this study to potentially support registration. We earned $40
        million in payments from Biogen in the fourth quarter of 2018 when Biogen advanced and licensed IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The depth of our knowledge and expertise
            with antisense technology together with our strong financial position provides us the flexibility to partner our medicines at what we believe is the optimal time to maximize the near-term, mid-term and long-term value of our medicines. </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have a distinct partnering strategy based on each specific medicine and the expertise and resources we and our potential partners may bring to a collaboration. We may
            develop and commercialize some medicines through affiliates. In general, these are medicines, like TEGSEDI, that can benefit from our internal expertise and infrastructure, have manageable development costs and have the potential for initial
            rare disease indications. For other medicines, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">we may establish collaborations to advance the medicine. We have alliances with a cadre of leading global
            pharmaceutical companies that are working alongside us in developing our medicines, advancing our technology, preparing to commercialize our medicines and selling our medicines. Our partners include the following companies, among others:
            AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis and Roche. Our partners bring resources and expertise that augment and build upon our internal capabilities. </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For





            example, we partnered AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> with Novartis because we believe Novartis brings significant resources and expertise that should accelerate
            our ability to deliver AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">to the </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">large population
            of patients with&#160; elevated levels of Lp(a) and established CVD.</font> As a result of Novartis exercising its option for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in February 2019, Novartis is responsible for conducting and funding all future development and commercialization activities, including a Phase 3 cardiovascular outcomes
            study Novartis is planning to conduct. We are eligible to </font>earn additional payments from Novartis as AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> progresses.</font></div>
    </div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are now a multi-product commercial company. 2018 marks our seventh consecutive year of revenue growth. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Through our partnerships, we have earned significant commercial revenue and a broad and sustaining base of research and development, or R&amp;D, revenue in the form of license
          fees, upfront payments and milestone payments, while investing in advancing our pipeline and technology. Moreover, we have the potential to earn over $20 billion in future milestone payments and licensing fees from our current partnerships. We
          also have the potential to share in the future commercial success of our inventions and drugs resulting from our partnerships through royalty arrangements. </font>Looking forward, we believe we have the potential to increase our commercial
        revenue from SPINRAZA royalties and TEGSEDI product sales from the continued growth we anticipate in the U.S., EU and other markets globally. We also have the potential to further increase our commercial revenue with the potential approval of
        WAYLIVRA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We ended 2018 with a strong balance sheet with more than $2 billion in cash and short-term investments, making this the
        sixth year out of seven that we have been cash accretive. Our strong balance sheet provides us with the financial wherewithal to invest in expanding and advancing our pipeline, in commercializing our medicines through commercial affiliates, and
        advancing our technology.</font></div>
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    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Our Marketed Medicines &#8211; Transformational Medicines Bringing Value to Patients Today</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">SPINRAZA </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8211; SPINRAZA (nusinersen) injection for intrathecal use is a survival motor neuron-2, or SMN2, directed antisense oligonucleotide indicated for the treatment of SMA in pediatric
          and adult patients. SPINRAZA is the first and only approved medicine for the treatment of SMA and is the established standard-of-care for all people around the globe with this progressive, debilitating genetic disease. </font>SPINRAZA is
        approved in over 40 countries around the world. In February 2019, SPINRAZA was approved by the China National Medical Products Association. Our partner, Biogen, who is responsible for global SPINRAZA commercial activities, reported in January 2019
        that approximately 6,600 patients were on SPINRAZA therapy. Biogen reported 2018 annual sales of more than $1.7 billion, and we earned $238 million in commercial revenues from royalties on sales of SPINRAZA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 40.5pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SMA is characterized by loss of motor neurons in the spinal cord and lower brain stem, resulting in severe and
        progressive muscular atrophy and weakness. Ultimately, individuals with the most severe type of SMA, infantile-onset, or Type 1, SMA, can become paralyzed and have difficulty performing the basic functions of life, like breathing and swallowing.
        Due to a loss of, or defect in, the SMN1 gene, people with SMA do not produce enough survival motor neuron, or SMN, protein, which is critical for the maintenance of motor neurons. The severity of SMA correlates with the amount of SMN protein a
        patient can produce on his/her own. Patients with Type 1 SMA produce very little SMN protein and do not achieve the ability to sit without support or live beyond two years without respiratory support. Patients with later-onset, or Type 2 or Type 3
        SMA, produce greater amounts of SMN protein and have less severe, but still life-altering, forms of SMA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA was recognized with the 2018 International Prix Galien Best Biotechnology Product award. The prestigious honor
        marks the seventh Prix Galien award for SPINRAZA, following country recognitions in the U.S., Germany, Italy, Belgium-Luxembourg, the Netherlands and the U.K. The International Prix Galien award is given every two years by Prix Galien International
        Committee members in recognition of excellence in scientific innovation to improve human health.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Biogen is conducting NURTURE, a Phase 2 open-label study of SPINRAZA in pre-symptomatic infants. Biogen presented an
        interim analysis of the NURTURE data at the Annual Congress of the World Muscle Society in October 2018. The interim analysis showed that SPINRAZA-treated infants achieved motor milestones in timelines more consistent with normal development than
        what is observed in the natural history of patients with Type 1 SMA. At the time of the interim analysis, all patients were alive and did not require respiratory intervention. All of the infants in the study were able to sit without support and 88
        percent of the infants were able to walk either with assistance or independently. No new safety concerns were identified.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The safety and efficacy of SPINRAZA has been evaluated in multiple clinical studies in more than 270 patients, including
        two Phase 3 studies: ENDEAR, a randomized controlled study evaluating SPINRAZA in patients with infantile-onset SMA, and CHERISH, a randomized controlled study evaluating SPINRAZA in patients with later-onset SMA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the ENDEAR end of study analysis, or EOS, a statistically significant greater percentage of children with
        infant-onset SMA achieved improvement in motor milestones compared to untreated patients, with some infants in the SPINRAZA group achieving full head control, the ability to roll, sit, and stand. Additionally, infants treated with SPINRAZA
        demonstrated a statistically significant improvement in event-free survival compared to untreated patients.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the CHERISH </font>EOS<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> there was a statistically significant and clinically meaningful improvement in motor function in children with later-onset SMA treated with SPINRAZA compared to untreated
          children. The majority of children treated with SPINRAZA demonstrated benefits in upper limb and general motor function, including crawling and standing with support. The overall findings from the CHERISH EOS analysis continue to support the
          robust efficacy and favorable safety profile of SPINRAZA across a broad patient population.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In all clinical studies, SPINRAZA
          demonstrated a favorable safety profile. The most common side effects of SPINRAZA included lower and upper respiratory infections, constipation, headache, back pain, and post-lumbar puncture syndrome. For additional safety information, please see
        </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">www.spinraza.com</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;">(Any information that is included on or linked to this website is not part of this report or any registration statement or report that incorporates this report by reference).</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">TEGSEDI &#8211; </font>TEGSEDI





        (inotersen) injection is a Generation 2+ antisense medicine and the world&#8217;s first and only approved subcutaneous RNA-targeting medicine designed to treat people with polyneuropathy caused by hATTR. In October 2018, the FDA approved TEGSEDI for the
        treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. TEGSEDI is also approved in the EU and Canada for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin
        amyloidosis. It is administered as a once weekly, self-administered, at-home, subcutaneous injection. In March 2018, Akcea licensed TEGSEDI from us.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TTR amyloidosis that is the result of inherited mutations in the TTR gene is referred to as hATTR. There are an
        estimated 50,000 people worldwide with hATTR. There are two primary manifestations of hATTR: polyneuropathy and cardiomyopathy. Many people with hATTR often experience both manifestations, but often one manifestation or the other is diagnosed first
        and is more pronounced.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In people with hATTR, both the mutant and wild type, or wt, TTR protein builds up as fibrils in the tissues, such as
        peripheral nerves, heart, gastrointestinal system, eyes, kidneys, central nervous system, thyroid and bone marrow. The presence of TTR fibrils interferes with the normal function of these tissues. As the TTR protein fibrils enlarge, more tissue
        damage occurs and the disease worsens, resulting in poor quality of life and eventually death. We designed TEGSEDI to reduce the production of the TTR protein, the underlying cause of transthyretin amyloidosis, or ATTR.</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Polyneuropathy due to hATTR is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves.
        People with polyneuropathy due to hATTR experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of sensation in the extremities that advances centrally, and loss of motor functions, such as walking.
        These people also accumulate TTR in other major organs, which progressively compromises their function and eventually leads to death within five to 15 years of disease onset. Cardiomyopathy caused by <font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;">ATTR</font> is the accumulation of misfolded TTR protein in the cardiac muscle.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">ATTR can also result from normal, non-mutant, TTR protein forming fibrils, primarily in the heart. This form of the
        disease is wt-ATTR. It is estimated that more than 200,000 people worldwide have wt-ATTR. People with hATTR cardiomyopathy and wt-ATTR experience ongoing debilitating heart damage resulting in progressive heart failure, which results in death
        within three to five years from disease onset.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The TEGSEDI approval relied on results from the Phase 3 NEURO-TTR study in patients with hATTR amyloidosis with stage 1
        and stage 2 polyneuropathy. Results from that study demonstrated that patients treated with TEGSEDI experienced significant benefit compared to patients treated with placebo across both co-primary endpoints: the Norfolk Quality of Life
        Questionnaire-Diabetic Neuropathy, or Norfolk QoL-DN, and modified Neuropathy Impairment Score +7, or mNIS+7, a measure of neuropathic disease progression.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> In July 2018,
          the final results from the NEURO-TTR pivotal study were published in </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">The New England Journal of Medicine.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Thrombocytopenia and safety signals related to renal function were identified during the study. Enhanced monitoring was
        implemented during the study to support early detection and management of these issues. Serious platelet and renal events were infrequent and manageable with routine monitoring, which has proven effective since implementation.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additionally, at the 60<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup> American Society of Hematology, or ASH, Annual Meeting and Exposition held in
        December 2018, we presented data from the open-label extension study, or OLE, in patients with hATTR treated with TEGSEDI. The OLE is an ongoing study and is intended to evaluate the long-term efficacy and safety profile of TEGSEDI. The benefits
        observed from TEGSEDI in the NEURO-TTR study continued in the OLE. In addition, the OLE results demonstrated that patients who initiated TEGSEDI treatment at the start of the NEURO-TTR study, 15 months earlier, experienced greater benefit than
        those who received placebo treatment in the NEURO-TTR study and then initiated treatment in the OLE. Patients who began the NEURO-TTR study on placebo experienced a rapid onset of effect following TEGSEDI treatment that has been sustained for up to
        2 years in the OLE. These patients further experienced improvements in quality of life and activities of daily living as measured by Norfolk QoL-DN and showed improved mNIS+7 progression compared to their rate of progression in the NEURO-TTR study.
        Specifically, these patients experienced a mean increase in Norfolk QoL-DN of 16.8, a 10 point improvement over projected placebo values and a mean increase in mNIS+7 of 34 points from baseline, a 24 point improvement over projected placebo values.
        No new safety concerns were identified in the OLE.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The product label for TEGSEDI in the U.S.
          has a boxed warning for thrombocytopenia and glomerulonephritis and requires periodic blood and urine monitoring. TEGSEDI has a Risk Evaluation and Mitigation Strategy, or REMS, program. </font>For TEGSEDI&#8217;s full prescribing information,
        including boxed warnings, please see <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">www.tegsedi.com</font> (Any information that is included on or linked to this website is not part of this report or any registration
        statement or report that incorporates this report by reference).</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We developed TEGSEDI under a collaboration agreement we had with GSK. Under the agreement, we are required to pay GSK a
        nominal royalty on net sales of TEGSEDI.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">See our separate section below where we further discuss Akcea, our affiliate focused on developing and commercializing
        medicines to treat people with serious and rare diseases.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:b94b94d0-336b-4ce4-87f8-ae16c3e2129f">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Drug Discovery and Development</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Introduction to Drug Discovery</font></div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Proteins are essential working molecules in a cell. Almost all human diseases result from inappropriate protein
        production, improper protein activity or loss of a protein. Antisense medicines can modify the production of proteins by targeting RNAs. In this way, antisense medicines can reduce the production of a disease-causing protein, modify the protein
        produced or increase the production of a protein that, when absent, causes diseases. Antisense medicines also can treat diseases by targeting and reducing RNAs that may be causing diseases (so called &#8220;toxic RNAs&#8221;). RNAs are naturally occurring
        molecules in the body that primarily act as messengers that carry the information the cell needs to produce proteins from the DNA/genes to the protein making complex in the cell. When our antisense medicines bind to the specific RNAs of a
        particular gene, they will ultimately alter the production of the protein encoded in the target gene or, in the case of disease-causing RNAs, degrade the toxic RNA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Our Development Projects</font></div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are a leader in the discovery and
          development of an exciting class of RNA-targeted medicines called antisense oligonucleotide, or ASO, medicines, or just antisense medicines. With our proprietary drug discovery platform, we can rapidly identify medicines from a wealth of
          potential targets to treat a broad range of diseases. We focus our efforts in therapeutic areas in which our medicines will work best, efficiently screening many targets in parallel and carefully selecting the best candidates. By combining this
          efficiency with our rational approach to selecting disease targets, we have built a large and diverse portfolio of medicines we designed to treat a variety of health conditions, such as cardiometabolic diseases, neurodegenerative diseases,
          cancer, severe and rare diseases and others.</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are developing antisense medicines for systemic and local delivery (e.g., intrathecal, intraocular, oral and
          aerosol).</font></font></div>
    <div><br>
    </div>
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We plan to continue to add new medicines to our pipeline, building a broad proprietary portfolio of medicines to treat
        many diseases and creating opportunities to generate substantial revenue. We also continue to improve our scientific understanding of our medicines, including how our medicines impact the biological processes of the diseases we target.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">With our expertise in discovering and characterizing novel antisense medicines, our scientists can optimize the
        properties of our antisense medicines against each particular target. Our scientists have made significant advances in chemical modifications we use in our antisense medicines, such as with our Generation 2+ antisense medicines, which have
        increased potency and an improved side effect profile over our earlier generation medicines. Our scientists have further improved upon our second-generation chemistry with our Generation 2.5 chemistry, an advancement that further increases the
        potency of our medicines, which broadens the organs and tissues in which our medicines can work. We currently have 13 Generation 2.5 medicines in development, and we anticipate that more of our future medicines will incorporate our Generation 2.5
        chemistry.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In addition to improving the chemical foundation of our medicines, we have also created LIgand-Conjugated Antisense, or
        LICA, technology, which we design to enhance the effective uptake and activity of our medicines in particular tissues. With our LICA technology we attach specific chemical structures or molecules to our antisense medicines. With our first LICA
        conjugate, a complex sugar-like molecule called N-acetylgalactosamine, or GalNac, we have shown an increase in medicinal potency of over 30-fold for liver targets, compared to non-conjugated antisense medicines. We currently have 13 LICA medicines
        in development, including two medicines that combine our Generation 2.5 chemistry and LICA technology.</font></div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have utilized our chemistry advancements, such as Generation 2.5 and LICA, to expand the therapeutic and commercial
        opportunities of our pipeline. These advancements, along with the manufacturing and analytical processes that are the same for all of our medicines, shorten our timeline from initial concept to the first human dose, when compared to early
        development timelines for other drug modalities like small molecule and antibody drugs.</font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><img width="710" height="510" src="image01.jpg"></div>
    <div><br>
    </div>
    <div style="text-align: center;"><img width="674" height="38" src="image02.jpg"></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The above table lists the medicines in our pipeline that are in registration for marketing authorization or in clinical
        trials. The table includes the disease indication, a partner (if the medicine is partnered), and the development status of each medicine. Typically, the names of our medicines incorporate the target of the medicine. For example, with IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>,
        the RNA produced from the huntingtin gene, represented by the acronym HTT, is the target of the medicine. Unless indicated otherwise, the majority of medicines in our pipeline are Generation 2+ antisense medicines. We differentiate medicines
        discovered at Ionis but being developed by Akcea by using &#8220;AKCEA&#8221;, instead of &#8220;IONIS&#8221; at the beginning of the medicine name, such as AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. We differentiate our Generation 2.5 medicines by adding a &#8220;2.5&#8221; notation at the end
        of the medicine name, such as IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. We differentiate our LICA medicines by adding an &#8220;L&#8221; at the end of the medicine name, such as IONIS-PKK-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. As the medicines in our pipeline advance in clinical development, we
        will adopt nonproprietary names given to each medicine from the U.S. Adopted Names Council. For example, inotersen is a nonproprietary name that we obtained for IONIS-TTR<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. Once we or our partners establish a brand name, we will adopt
        the brand name. For example, TEGSEDI is the brand name for inotersen.</font></div>
    <div><br>
    </div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">With a pipeline as large and advanced as ours, we have a number of clinical events each year as we initiate new clinical
        studies, complete and report data from clinical studies, and add numerous new medicines to our pipeline.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">WAYLIVRA &#8211; Potential Approval in Europe Following Positive CHMP Opinion</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">WAYLIVRA (volanesorsen)
          &#8211; </font>WAYLIVRA is a Generation 2+ antisense medicine we and Akcea are developing to treat people with FCS and FPL, which are severe, rare, genetically defined diseases characterized by extremely elevated triglyceride levels and a high risk of
        life-threatening pancreatitis. We are preparing to commercialize WAYLIVRA in the EU.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2019, the CHMP of the EMA adopted a positive opinion recommending conditional marketing authorization for
        WAYLIVRA as an adjunct to diet in adult patients with genetically confirmed FCS who are at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate. The positive opinion will now be referred to the
        EC, which grants marketing authorization for medicines in the EU, as well as to European Economic Area members Iceland, Liechtenstein and Norway. With this positive opinion, and, pending adoption of the positive opinion by the EC, Akcea plans to
        leverage its existing commercial infrastructure in Europe to market WAYLIVRA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In August 2018, we received a complete response letter, or CRL, from the Division of Metabolism and Endocrinology
        Products of the FDA regarding the NDA for WAYLIVRA. We are continuing our discussions with the FDA regarding WAYLIVRA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Due to the high levels of triglycerides in their blood, people with FCS may suffer from many chronic health issues
        including severe, recurrent abdominal pain, fatigue, high risk of life-threatening pancreatitis and abnormal enlargement of the liver or spleen. It is estimated to affect 3,000 to 5,000 people in treatable markets. In addition, people with FCS must
        adhere to a very strict, low-fat diet. FPL is a rare, orphan disease that is estimated to affect 3,000 to 5,000 patients worldwide. Patients with FPL typically have diabetes and other metabolic abnormalities, including elevated triglycerides, which
        increases their risk of pancreatitis. As a result of these factors, people with FCS and FPL are often unable to work, adding to the burden of these diseases. In severe cases, patients can have bleeding into the pancreas, serious tissue damage,
        infection and cyst formation, as well as damage to other vital organs such as the heart, lungs and kidneys.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">WAYLIVRA acts to reduce triglyceride levels by inhibiting the production of apolipoprotein C-III, or apoC-III, a protein
        that is a key regulator of triglyceride levels. People who have low levels of apoC-III or reduced apoC-III function have lower levels of triglycerides and a lower incidence of CVD. By inhibiting the production of apoC-III, WAYLIVRA is able to
        reduce their triglyceride levels.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The marketing authorization application for WAYLIVRA <font style="background-color: #FBFBFB; font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">is based on results from the Phase 3 APPROACH study and the ongoing APPROACH Open Label Extension, or OLE, study and supported by results from the Phase 3 COMPASS study.</font> The pivotal APPROACH
        study, a one-year, randomized, placebo-controlled study in 66 patients with FCS (average baseline triglycerides of 2,209 mg/dL, or 25.0 mmol/L), achieved its primary endpoint of reduction in triglycerides at three months, with a 77 percent mean
        reduction in triglycerides, which translated into a 1,712 mg/dL (19.3 mmol/L) mean absolute triglyceride reduction in WAYLIVRA-treated patients. We observed 50 percent of treated patients achieved triglyceride levels below 500 mg/dL, a commonly
        accepted threshold for pancreatitis risk. In addition, in the APPROACH study, treatment with WAYLIVRA was associated with a statistically significant reduced rate of pancreatitis attacks in the group of patients who had the highest incidence of
        pre-study pancreatitis and reduced abdominal pain in patients reporting pain before treatment in the study.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The most common adverse event in the studies was injection site reactions, which were mostly mild. In addition, declines
        in platelet counts were observed in many patients and some patients discontinued the study because of platelet declines. These platelet declines were not clinically significant in most patients and were generally well managed with monitoring and
        dose adjustment. Some patients discontinued participation in the APPROACH study due to other non-serious adverse events, including sweating and chills, severe fatigue, rash and injection site reaction. In the APPROACH study and the open-label
        extension study, the potentially treatment- related serious adverse events, or SAEs, observed were serious platelet events (grade 4 thrombocytopenia), which resolved without complication after cessation of dosing. Enhanced monitoring was
        implemented during the study to support early detection and management of these issues. Since implementation of the enhanced monitoring, serious platelet events have been infrequent. The COMPASS study, a six-month randomized placebo-controlled
        study in 113 patients with very high triglycerides (&gt;500 mg/dL), also achieved its primary endpoint of reduction in triglycerides at three months, with a 71 percent mean reduction in triglycerides. In the COMPASS study, treatment with WAYLIVRA
        was associated with a statistically significant reduction in on-study pancreatitis attacks. The most common adverse event in the WAYLIVRA-treated group of patients was injection site reactions, which were mostly mild. In addition, a potentially
        treatment-related SAE of serum sickness reaction, from which the patient fully recovered, was reported. There have been no deaths and no treatment-related bleeding or cardiovascular events in any WAYLIVRA clinical study.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are conducting the BROADEN study, a Phase 3 clinical trial in patients with FPL, with data anticipated this year.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">An open-label extension study is ongoing for patients with FCS who have completed or meet the study criteria for the
        APPROACH and COMPASS studies. Additionally, we have expanded access programs, or EAPs, for WAYLIVRA. Patients in the BROADEN study are also eligible to roll over into an open-label extension study upon completing dosing in the pivotal study. We
        plan to commercialize WAYLIVRA through Akcea for patients with FCS and FPL, if approved in other markets.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Potential Next Wave of Pivotal Medicines</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Focusing on our key fundamental strategies has created a deep and broad pipeline of over 40 first-in-class and/or
        best-in-class medicines that we believe have the potential to deliver significant value to patients affected by these devastating diseases, many of which have limited treatment options. We have at least four medicines that have begun pivotal
        studies or have the potential to begin pivotal studies this year.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(TQJ230)





          &#8211; </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">is a Generation 2+ LICA medicine we designed to reduce the production of apolipoprotein(a), or Apo(a), protein in the liver to offer a direct approach for reducing
          lipoprotein(a), or Lp(a). Lp(a) is an independent risk factor for CVD that is composed of an apolipoprotein(a) protein bound to an LDL-cholesterol particle. Akcea initiated a collaboration with Novartis in January 2017 to advance AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea is developing AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for people who are at significant risk of CVD because of their elevated
        levels of Lp(a). AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> inhibits the production of the Apo(a) protein, thereby reducing Lp(a). Lp(a) is a very atherogenic and thrombogenic form of LDL. Elevated Lp(a) is recognized as an independent, genetic cause of coronary
        artery disease, heart attack, stroke and peripheral arterial disease. Inhibiting the production of Apo(a) in the liver reduces the level of Lp(a) in blood, potentially slowing down or reversing cardiovascular disease in people with
        hyperlipoproteinemia(a), a condition in which individuals have levels of Lp(a) greater than 50 mg/dL.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Lp(a) is difficult to inhibit using other technologies, such as small molecules and antibodies. There are multiple
        genetically-determined forms of the Apo(a) molecule and creating a small molecule or antibody that can interact with multiple targets is difficult. We believe antisense technology is well suited to address hyperlipoproteinemia(a) because antisense
        technology specifically targets the RNA that codes for all forms of the Apo(a) molecule. As a result, it can stop the production of all the forms of the protein. Furthermore, we believe addressing elevated Lp(a) is the next important horizon in
        lipid-focused treatment.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We reported results of the Phase 2 study with AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in patients with hyperlipoproteinemia(a) at the
        American Heart Association, or AHA, annual meeting in November 2018. In this clinical study, we observed statistically significant and dose dependent reductions from baseline in Lp(a) levels. Approximately 98 percent of patients who received the
        highest dose in the study demonstrated a reduction in Lp(a) levels to below 50 mg/dL, the recognized threshold for risk of CVD. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">This study of AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> was </font>the longest and largest clinical study in patients with established CVD and elevated levels of Lp(a). This study was also the longest and largest clinical study
        of any of our LICA medicines. AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated a favorable safety and tolerability profile in the study. Compliance in the study was almost 90 percent, which was higher than what we observed in the placebo group.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2019, Novartis exercised its option to license AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and Novartis&#8217; preparations to
        initiate Phase 3 a cardiovascular outcomes study are already underway</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-TTR-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#8211;
        </font>We are co-developing AKCEA-TTR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> with Akcea to inhibit the production of transthyretin, the same protein inhibited by TEGSEDI (inotersen). There are two types of ATTR amyloidosis: hATTR amyloidosis and wt-ATTR amyloidosis.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are developing AKCEA-TTR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for the treatment of people with all forms of TTR amyloidosis as a once a month
        or even less frequent subcutaneous self-administered injection. We plan to report data from the Phase 1/2 study this year, followed by the initiation of a pivotal program. We plan to initiate a Phase 3 study in patients with hereditary TTR
        amyloidosis with polyneuropathy first, followed closely by a Phase 3 study in patients with wild type and hereditary TTR cardiomyopathy, also planned for this year.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-HTT</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211; </font>IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> (RG6042) is a Generation 2+ antisense medicine we designed to target the
        underlying cause of HD by reducing the production of the toxic mHTT protein. Roche initiated the Phase 3 study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for Huntington&#8217;s disease, or HD, in December 2018 and the first patient was dosed in the Phase 3 study in
        January 2019. In addition to the Phase 3 study, all participants who took part in the Phase 1/2 study are eligible to continue to receive IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> as part of an OLE study to assess the safety and tolerability of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.
        In parallel with the Phase 3 study and the OLE, Roche initiated a natural history study in a similar patient population to the OLE. The natural history study is planned as a 15-month observational study aimed at further understanding the role of
        mHTT in disease progression and is anticipated to include up to 100 participants with Stage I and II HD. There is no drug treatment in the observational study, as the goal is to understand the natural progression of HD.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We completed a randomized, placebo-controlled, dose escalation, Phase 1/2 clinical study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in
        patients with early stage HD. In this study, we observed dose-dependent reductions of mHTT among patients treated with IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated a favorable safety and tolerability profile. In March 2018, we
        reported data from the study that demonstrated up to a 60 percent reduction in the mHTT as observed in the CSF. It was the first study to demonstrate disease-modifying potential. The mHTT reductions of 40-60 percent in the CSF correspond to an
        estimated 55-85 percent reduction in the cortex of the brain, where mHTT is highly expressed, based on preclinical data. There were no serious adverse events reported and no participants discontinued from the study. In August 2018, the EMA granted
        PRIME designation to IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. EMA PRIME status is granted to medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options. The FDA and EMA granted Orphan Medicine
        Designation for IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to treat people with HD.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">HD is a rare, inherited, genetic brain disorder that results in the progressive deterioration of mental abilities and
        physical control. In the U.S., there are approximately 30,000 individuals with symptomatic HD and more than 200,000 people at risk of inheriting HD. HD is a triplet repeat disorder and is one of a large family of genetic diseases in which the body
        mistakenly repeats certain gene sequences. The resulting mHTT protein is toxic and gradually damages neurons in the brain. Symptoms of HD usually appear between the ages of 30 to 50 years and continually worsen over a 10 to 25-year period.
        Ultimately, the weakened individual succumbs to pneumonia, heart failure or other complications. Presently, there are no disease-modifying treatments available for HD patients, with current drugs only managing some disease symptoms.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We entered into a collaboration with Roche to develop and commercialize antisense medicines to treat HD in April 2013.
        In December 2017, Roche exercised its licensing option to develop and commercialize IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> following the completion of a Phase 1/2 randomized, placebo-controlled, dose escalation study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>&#160;in people with HD.
        Roche is responsible for all IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> development, regulatory and commercialization activities and costs.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-SOD1</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> (BIIB067) &#8211; </font>IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> is a Generation 2+ antisense medicine we designed to reduce
        the production of superoxide dismutase 1, or SOD1, which is a well understood genetic cause of familial amyotrophic lateral sclerosis, or ALS. We are collaborating with Biogen to develop IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to treat people with an inherited
        form of ALS, SOD1-ALS.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">ALS is a rare, fatal, neurodegenerative disorder. People with ALS suffer progressive degeneration of the motor neurons,
        which results in a declining quality of life and ultimately death. The second most common familial form of ALS is SOD1-ALS, in which people have a mutation in the SOD1 gene that causes a progressive loss of motor neurons. As a result, people with
        SOD1-ALS experience muscle weakness, loss of movement, difficulty breathing and swallowing and eventually succumb to the disease. Currently, treatment options for people with ALS are extremely limited, with no medicines that significantly slow
        disease progression.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2018, Biogen exercised its licensing option to develop and commercialize IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> based on
        the positive interim analysis from the Phase 1/2 study that demonstrated proof-of-biology and proof-of-concept. Biogen is responsible for all IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> development, regulatory and commercialization activities and costs. At the highest
        dose tested, treatment with IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> over a three month period resulted in a statistically significant lowering of SOD1 protein levels in the CSF and positive numerical trends across three efficacy endpoints: slowing of clinical
        decline as measured by the ALS functional rating scale-revised, slowing of decline in respiratory function as measured by vital capacity and slowing of decline in muscle strength as measured by a handheld device, all compared to placebo. The safety
        and tolerability profile in this study supports the continued development of IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in ALS.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Biogen plans to add an additional cohort to this study to potentially support registration of IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Neurological Disease Franchise</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are discovering and developing antisense medicines to treat people with inadequate treatment options for both common
        and rare neurological diseases. According to the National Institute of Neurological Disorders and Stroke, or NINDS, at the National Institutes of Health, or NIH, a third of the 7,000 known rare diseases are neurological disorders or thought to
        include a neurological component.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Neurological Disease Clinical Pipeline</font></font></div>
    <div style="text-align: center;"><img width="710" height="148" src="image04.jpg"></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-HTT</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; See the medicine description under &#8220;Next Wave of Pivotal Medicines&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-TTR-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>&#8211; See the medicine description under &#8220;Next Wave of Pivotal Medicines&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-SOD1</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; See the medicine description under &#8220;Next Wave of Pivotal Medicines&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-MAPT</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; IONIS-MAPT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> is a Generation 2+ antisense medicine we designed to selectively reduce production of the tau protein in the brain. We are collaborating with Biogen to develop IONIS-MAPT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        to treat people with Alzheimer&#8217;s disease, or AD, and frontotemporal dementia, or FTD, common forms of dementia.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Microtubule-associated protein tau, or tau, is a contributor or cause of certain neurodegenerative diseases, known as
        tauopathies, characterized by the deposition of abnormal tau protein in neurons and non-neuronal cells in the brain. AD and FTD are characterized by predominant memory impairment and behavioral changes, resulting in a person&#8217;s inability to
        independently perform daily activities. AD generally occurs late in life and may progress to death in five to 20 years after the onset of the disease. FTD has a more rapid disease progression. There are approximately five million people living with
        AD in the U.S. and approximately 55,000 people affected by FTD in the U.S.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We and Biogen are evaluating IONIS-MAPT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in a Phase 1/2 double-blind, randomized, placebo-controlled,
        dose-escalation study to evaluate the safety and activity of once-monthly intrathecal injections in patients with mild AD. We are planning to report data from this study in 2020.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-C9</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; IONIS-C9<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, also referred to as BIIB078, is a Generation 2+ antisense medicine we designed to selectively reduce the production of the mutated chromosome 9 open reading frame 72, or
        C9ORF72, gene. A mutation in this gene results in an inherited form of ALS, referred to as C9ORF72-ALS, the most prevalent genetic cause of ALS worldwide. There is substantial evidence that this mutation is responsible for a toxic gain of function
        repeat expansion that can lead to rapid progressive loss of motor neurons in people with C9ORF72-ALS. This is a fatal disease characterized by muscle weakness, loss of movement, and difficulty breathing and swallowing. We believe IONIS-C9<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        represents a novel approach to targeting ALS, for which there is no cure.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We and Biogen are collaborating to develop IONIS-C9<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to treat patients with this form of ALS. In August
        2018, we initiated a Phase 1/2 clinical study evaluating IONIS-C9<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in patients with C9ORF72-ALS. The current study is a randomized, blinded, placebo-controlled study designed to assess the safety, tolerability, and pharmacokinetics of
        multiple ascending doses of IONIS-C9<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> administered intrathecally to adults with C9ORF72-ALS. IONIS-C9<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> is the second medicine from our Biogen collaboration targeting a familial form of ALS. The first is IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>,
        designed to treat SOD1 related ALS, caused by a mutation in the SOD1 gene.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Severe and Rare Disease Franchise</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our severe and rare disease franchise is one the largest franchises in our pipeline. We are discovering and developing
        antisense medicines to treat people with severe and rare diseases who need new treatment options. We believe our antisense technology could offer effective therapies for these people. According to the NIH there are approximately 7,000 rare
        diseases, many life-threatening or fatal. Unfortunately, people with many of these severe and rare diseases have few effective therapies available. Since most of these diseases are genetic or have a genetic component, parents often pass the disease
        to their children, creating a legacy of the disease resulting in profound effects on the family. Due to the severe nature of these diseases and the lack of available treatments, there is an opportunity for more flexible and efficient development
        paths to the market. For example, SPINRAZA was approved five years after we began the Phase 1 study for it.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Severe and Rare Disease Clinical Pipeline</font></font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><img width="710" height="221" src="image05.jpg"></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">WAYLIVRA</font> - See
        the medicine description under &#8220;WAYLIVRA - Under Regulatory Review for Marketing Authorization&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-TTR-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; See the medicine description &#8220;Next Wave of Pivotal Medicines&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-GHR-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; IONIS-GHR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> is a Generation 2+ LICA medicine we designed to reduce the production of the growth hormone receptor, or GHr, to decrease the circulating level of insulin-like growth
        factor-1, or IGF-1. IGF-1 is a hormone primarily produced in the liver that plays an important role in childhood growth and has anabolic effects in adults. Several different diseases result from abnormally low or high levels of IGF-1, or an
        inappropriate response to this hormone. When produced in excess, IGF-1 results in acromegaly, a chronic, and life-threatening disease.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">High levels of circulating GH and IGF-1 lead to this multisystem disease characterized by organ overgrowth and physical
        disfigurement, such as enlarged hands, feet, and facial features. Patients with acromegaly also experience multiple co-morbidities, such as type 2 diabetes, hypertension, and respiratory complications, as well as premature mortality. Because IGF-1
        mediates the majority of the growth-promoting action of GH, reducing GHr production could in turn decrease levels of IGF-1 and provide a potential treatment to patients with acromegaly. Acromegaly is a rare disease with an estimated 25,000 patients
        in the U.S. Current treatments to block IGF-1 include surgical removal of the pituitary gland, which is often unsuccessful. Drug treatments to normalize IGF-1 levels are also available but are associated with potentially serious side effects.</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have completed a Phase 1, double-blind, placebo-controlled, dose-escalation study of IONIS-GHR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in
        healthy volunteers. In this study, IONIS-GHR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated a favorable safety and tolerability profile. There were no reports of deaths, serious adverse events or adverse events that led to study discontinuation. IONIS-GHR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        has the potential to bring substantial benefit to patients with acromegaly with at home, monthly subcutaneous administration.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In November 2018, we initiated the Phase 2 proof of concept clinical study of IONIS-GHR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in acromegaly
        patients. The study is a randomized, double-blind, placebo-controlled, multi-center study in acromegaly patients uncontrolled on select long-acting somatostatin receptor ligands. Patients in the study will receive monthly subcutaneous injections
        for four months. We anticipate we will complete this study by the end of this year.</font></div>
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    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-TMPRSS6-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; IONIS-TMPRSS6-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> is a Generation 2+ LICA medicine we designed to reduce the production of transmembrane protease, serine 6, or TMPRSS6, to treat anemia and iron toxicity in people with
        &#946;-thalassemia, a disease caused by mutations in the beta globin gene. TMPRSS6 is a protein produced in the liver that is important in the regulation of the body&#8217;s iron homeostasis through the control of the iron regulatory protein hepcidin.
        Inhibition of TMPRSS6 leads to increased production of hepcidin, which results in more effective red blood cell production in the bone marrow and reduced iron toxicity in the liver as a result of improved control of iron availability.</font></div>
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    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Patients with &#946;-thalassemia can experience severe anemia, marrow expansion, bone deformities, as well as iron toxicity.
        While the severity of anemia varies between patients, iron toxicity is a common complication leading to high rates of mortality as a result of iron accumulation in major organs, such as the heart and liver. Currently there are no effective
        therapies for patients with &#946;-thalassemia. The current standard of care is managing patients&#8217; symptoms with blood transfusions, hydroxyurea, and iron chelation.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#946;-thalassemia can be further subdivided into patients with transfusion-dependent thalassemia, or TDT, and
        non-transfusion dependent thalassemia, or NTDT, including &#946;-thalassemia intermedia. Although transfusions are not needed to support life in patients with NTDT, the associated complications of the disease are severe and often fatal. There are
        approximately 20,000 people in North America and Europe who suffer from &#946;-thalassemia intermedia.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Results from preclinical and clinical studies suggest that reducing levels of TMPRSS6 may be an effective strategy to
        control iron availability, improve liver iron toxicity and increase red blood cell production under conditions of &#946;-thalassemia. In December 2018, we presented positive Phase 1 data at the ASH Annual Meeting. In a randomized, double-blind,
        placebo-controlled, dose-escalation Phase 1 study in healthy volunteers, we demonstrated dose-dependent reductions of serum iron and serum transferrin saturation. Additionally, we observed an increase in serum hepcidin and predicted changes in
        hemoglobin. IONIS-TMPRSS6-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated a favorable safety and tolerability profile.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are planning to begin the Phase 2 proof of concept study of IONIS-TMPRSS6-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> this year.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-PKK</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx </font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">and IONIS-PKK-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211; </font>IONIS-PKK<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-PKK-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> are antisense medicines we designed to reduce the production of prekallikrein, or PKK, to treat people with
        hereditary angioedema, or HAE. It is a rare genetic disease that is characterized by rapid and painful attacks of inflammation in the hands, feet, limbs, face, abdomen, larynx and trachea and can be fatal if swelling occurs in the larynx. PKK plays
        an important role in the activation of inflammatory mediators associated with acute attacks of HAE. By inhibiting the production of PKK, IONIS-PKK<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-PKK-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> could be effective prophylactic approaches to preventing
        HAE attacks. In patients with frequent or severe attacks, doctors may use prophylactic treatment approaches to prevent or reduce the severity of HAE attacks.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have completed a Phase 1 study evaluating IONIS-PKK<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in healthy volunteers and we are exploring potential
        development options. In this study, IONIS-PKK<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated a favorable safety and tolerability profile. We are currently evaluating IONIS-PKK-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in a Phase 1, randomized, double-blind, placebo-controlled, dose-escalation
        study in healthy volunteers. The Phase 1 study is evaluating single and multiple doses of IONIS-PKK-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> administered subcutaneously.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-ENAC-2.5</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211; </font>IONIS-ENAC-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif; font-weight: bold;">&#160;</font>is a Generation 2.5 antisense medicine we designed to selectively reduce epithelial sodium channel, or EnaC, to treat people with cystic fibrosis, or CF. CF is an autosomal recessive disorder caused by mutations
        in the gene that encodes the cystic fibrosis transmembrane conductance regulator, or CFTR. CFTR is a chloride channel expressed in epithelial cells, including those in the lung. Targeting ENAC may enable treatment of all forms of CF due to various
        CFTR mutations, unlike existing therapeutics. CF is a multisystem disease that mostly affects the lungs, clogging airways due to mucus build-up and resulting in inflammation and infection. This disease is characterized by a progressive decline in
        lung function with acute periods of worsened symptoms, known as pulmonary exacerbations. CF is estimated to affect approximately 30,000 people in the U.S. and another 70,000 worldwide. Despite progress with other treatments, there remains a need
        for effective treatment options.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense aerosol technology for lung delivery may provide a novel solution for targeting ENaC potentially enabling all
        patients with CF to be treated. In preclinical studies in transgenic rodents, treatment with ENaC-targeting antisense drugs specifically suppressed ENaC expression, resulting in the reduction of markers of CF mucus pathology and improved lung
        function. Treatment prevented manifestations of the disease from occurring and reversed existing CF.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2018, we initiated a Phase 1 study of healthy volunteers in a double-blinded, placebo-controlled,
        dose-escalation study to evaluate the safety and efficacy of IONIS-ENAC-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. The study will consist of four randomized single-dose cohorts and four multiple-dose cohorts.</font></div>
    <div><br>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Cardiometabolic and Renal Disease Franchise</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cardiovascular disease is an important area of focus for us. According to the World Health Organization, or WHO,
        cardiovascular disease was the number one cause of death globally. An estimated 17.9 million people died from CVD in 2016, representing 31 percent of all deaths globally. The medicines in our cardiovascular franchise target the key components of
        cardiovascular disease, including various atherogenic lipids, inflammation and thrombosis. Metabolic disorders are chronic diseases that affect tens of millions of people. There is a significant need for new therapies for these people. According to
        the Centers for Disease Control and Prevention, diabetes affects more than 30 million people in the U.S., or nine percent of the population, with type 2 diabetes constituting 90 percent of those cases.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Cardiometabolic and Renal Disease Clinical Pipeline</font></font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><img width="710" height="228" src="image06.jpg"></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-ANGPTL3-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8211; </font>AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>is a Generation 2+ LICA medicine we designed to reduce the production of the angiopoietin-like 3, or ANGPTL3, protein. We and Akcea are developing
        AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to treat nonalcoholic fatty liver disease, or NAFLD.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">People with elevated levels of the angiopoietin-like 3, or ANGPTL3, protein have high LDL-C and triglyceride levels.
        Studies show this elevation is associated with an increased risk of premature heart attacks, increased arterial wall thickness, increased liver fat and multiple metabolic disorders, such as insulin resistance. In contrast, people with lower levels
        of ANGPTL3 have lower LDL-C and triglyceride levels, and thus lower risk of heart attacks, lower prevalence of fatty liver and lower incidence of metabolic disorders.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In preclinical studies, an analog of AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> inhibited the production of the ANGPTL3 protein in the
        liver, resulting in lower liver fat accumulation and lower blood levels of LDL-C, triglycerides and very low-density lipoprotein cholesterol, or VLDL-C. In addition, our preclinical data and initial Phase 1 data suggest that inhibiting the
        production of ANGPTL3 could improve other lipid parameters, including triglyceride levels and total cholesterol, as well as metabolic parameters, such as insulin sensitivity.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have completed a Phase 1/2 program for AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in healthy volunteers with elevated
        triglycerides. Results for the initial cohort from this study were reported at the AHA meeting in November 2016 and the data were published in <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">The</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">New England Journal of Medicine</font>. We observed that the people with elevated triglycerides achieved dose-dependent, statistically significant mean
        reductions in ANGPTL3 of up to 83 percent. Treatment with AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> was also associated with statistically significant mean reductions in triglycerides of up to 66 percent, in LDL-C of up to 35 percent and in total cholesterol of
        up to 36 percent. In this study, AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated a favorable safety and tolerability profile.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the fourth quarter of 2017, we initiated a multicenter, randomized, double-blind, placebo-controlled dose-ranging
        study of AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">patients</font> with NAFLD with metabolic complications, which include hypertriglyceridemia, type 2 diabetes and nonalcoholic
        steatohepatitis, or NASH. We are planning to report data from this study in 2020.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Further, we have a small ongoing study of AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in <font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;">patients</font> with rare hyperlipidemias<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> and IONIS-FXI-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211; </font>IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-FXI-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> are antisense medicines we designed to reduce the production of Factor XI. Factor XI is a clotting factor produced in
        the liver that is important in the growth of blood clots. High levels of Factor XI increase the risk of thrombosis, which is the formation of a blood clot inside blood vessels. Thrombosis can cause heart attacks and strokes. People who are
        deficient in Factor XI have a lower incidence of thromboembolic events with minimal increase in bleeding risk. Although currently available anticoagulants reduce the risk of thrombosis, physicians associate these anticoagulants with increased
        bleeding, which can be fatal. Given the mechanism of Factor XI inhibition, we believe that our medicine can be used broadly as an anti-thrombotic in many different therapeutic settings for which additional safe and well tolerated anti-thrombotic
        medicines are needed.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We completed a Phase 2 open-label,
          comparator-controlled global study evaluating IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in people undergoing total knee replacement surgery. The study compared the safety and
          activity of IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> to enoxaparin. In this study patients treated with 300 mg of IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;"> experienced a seven-fold lower rate of venous thromboembolic events, such as blood clots in a deep vein or in a lung, compared to those patients treated with enoxaparin. In this study, IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>demonstrated a favorable safety and tolerability profile<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. The data from this study were
          published in </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">The New England Journal of Medicine</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in
          December 2014.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In May 2015, we exclusively licensed IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>to Bayer.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">14</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In November 2016, we completed a Phase 2
          double-blinded, randomized, placebo-controlled study of IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in people with end-stage renal disease on hemodialysis. In this Phase 2 study,
          patients treated with IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">achieved statistically significant, dose-dependent reductions in Factor XI activity. In this study, IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>demonstrated a favorable safety and tolerability profile.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> There were no treatment-related
          major or clinically relevant non-major bleeding events.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are currently evaluating IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in a Phase 2b study in people with end-stage renal disease on
        hemodialysis to finalize dose selection. We are planning to report data from this study this year.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2017, we amended our agreement with Bayer to advance <font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;">IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and</font> to initiate development of IONIS-FXI-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. We plan to develop IONIS-FXI-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>through
        Phase 1. The Phase 1 study is in progress in healthy volunteers. It is a double-blind, randomized, placebo-controlled, dose-escalation study that will assess the safety and efficacy of IONIS-FXI-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; See the medicine description under &#8220;Next Wave of Pivotal Medicines&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx </font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#8211; </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">&#160;</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">is a LICA medicine we designed to inhibit the production of apoC-III, the same protein inhibited by WAYLIVRA, for the broad
          population of people who are at risk for cardiometabolic disease due to their elevated triglyceride levels. </font>We and Akcea are developing AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.<font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif;"> ApoC-III impacts triglyceride levels and may also increase inflammatory processes. </font>This combination of effects makes apoC-III a promising target for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">people</font>
        with LDL-C already controlled on statin therapy, but for whom triglycerides remain poorly controlled. We believe that the enhancements offered by our LICA technology can provide greater patient convenience by allowing for significantly lower doses
        and less frequent administration, compared to WAYLIVRA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In October 2017, we reported positive results of a Phase 1/2 clinical study in healthy volunteers with elevated
        triglyceride levels. Patients in the study were treated with multiple doses at either weekly or monthly dosing intervals. Patients treated with AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated significant dose-dependent reductions in apoC-III protein and
        triglycerides. In this study, AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated a favorable safety and tolerability profile. No serious adverse events, platelet count reductions, changes in liver function or adverse events leading to treatment
        discontinuation were observed.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Novartis entered into a collaboration with
          us in January 2017 to advance AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. In the first quarter of 2018, we initiated a</font> Phase 2b dose-ranging study of AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        in <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">patients</font> with hypertriglyceridemia and established CVD. We plan to report data from this study in 2020.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-DGAT2</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx </font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#8211; </font>IONIS-DGAT2<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> is a Generation 2+ antisense medicine we designed to reduce the
        production of DGAT2, or diacylglycerol acyltransferase 2, to treat people with NASH. NASH is a common liver disease characterized by excessive triglycerides in the liver with concurrent inflammation and cellular damage. As NASH progresses,
        scarring, or fibrosis, begins to accumulate in the liver. Ultimately, cirrhosis of the liver develops. Currently, it is estimated that two to three percent of the general population have NASH. With the growing obesity epidemic, the number of people
        with NASH should also continue to rise. About 20 percent of people with NASH are reported to have a liver that does not function properly due to long-term damage, known as cirrhosis. Of those with NASH-related cirrhosis, 30 - 40 percent experience
        liver-related death. Currently, liver transplantation is the only treatment for advanced cirrhosis and liver failure. Because of the high prevalence of NASH, it has recently become the third most common indication for liver transplantation in the
        U.S.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">DGAT2 is an enzyme that catalyzes the final step in triglyceride synthesis in the liver. Reducing the production of
        DGAT2 should therefore decrease triglyceride synthesis in the liver. In animal models of obesity and fatty liver disease, antisense inhibition of DGAT2 significantly improved NAFLD, lowered blood lipid levels and reversed diet-induced insulin
        resistance. NASH is a more severe form of NAFLD.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS-DGAT2<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> was evaluated in a Phase 2 randomized, placebo-controlled, dose-escalation study in patients
        with type 2 diabetes and NAFLD. In December 2018, we reported that IONIS-DGAT2<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> substantially reduced liver fat after only three months of treatment. 50 percent of IONIS-DGAT2<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> treated patients had relative liver fat
        reductions of greater than or equal to 30 percent. IONIS-DGAT2<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated a favorable safety profile with no safety concerns related to the liver, kidney or platelets. Additionally, there were no increased levels of triglycerides or
        cholesterol. We plan to develop a liver LICA version of IONIS-DGAT2<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-AGT-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#8211;</font> IONIS-AGT-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> is a Generation 2+ LICA medicine we designed to reduce the production
        of angiotensinogen to decrease blood pressure in people with treatment resistant hypertension, or TRH. Despite the availability of generic antihypertensive agents, TRH is a major contributor to cardiovascular and renal disease.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Approximately 75 million adults in the U.S. have hypertension, half of whom have uncontrolled hypertension. About 12-15
        percent of patients with uncontrolled hypertension have resistant hypertension, defined as failure to achieve a blood pressure goal of 140/90 (systolic/diastolic) despite the use of three or more antihypertensive medications. Current estimates
        approximate that there are up to three million people with TRH in the U.S. People with TRH have been found to have a three-fold higher chance of having fatal and non-fatal cardiovascular events relative to those with controlled hypertension.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are evaluating IONIS-AGT-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in a double-blinded, randomized, placebo-controlled, Phase 2 study in people
        with mild hypertension.</font></div>
    <div><br>
    </div>
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      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">15</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Oncology Franchise and Other Medicines in Development</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cancer is an area of significant unmet medical need. Cancer is an extremely complex disease that involves a large number
        of targets. Using our antisense technology, we can validate multiple potential cancer targets from a variety of different cancers, and rapidly identify anti-cancer drugs, which in many cases are the same or similar sequences to those used to
        validate the target. We preferentially select anti-cancer targets that can potentially provide a multi-faceted approach to treating cancer.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our oncology franchise consists of anti-cancer antisense medicines that act upon biological targets associated with
        cancer progression, treatment resistance, and/or the tumor immune environment. We have a strategic alliance with AstraZeneca, which includes an anti-cancer collaboration that expands our anti-cancer efforts and supports a robust clinical
        development plan for danvatirsen and IONIS-AZ7-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. AstraZeneca brings significant experience that enables the identification of novel genetic and epigenetic targets for cancer. Combining AstraZeneca&#8217;s expertise with our drug discovery
        technology, we plan to expand our oncology franchise with a number of promising new anti-cancer targets. We also have a collaboration agreement with University of Texas MD Anderson Cancer Center to identify cancer targets and create novel antisense
        medicines to treat cancer together.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our Generation 2.5 chemistry enhances the potency and effectiveness of our antisense medicines, and potentially allows
        us to extend the applicability of our technology to cancers that are difficult to treat. For instance, STAT3 is a protein known to be important in carcinogenesis, however, it has been difficult to approach with traditional drug modalities. Data
        from a Phase 1b/2 clinical study of danvatirsen in combination with durvalumab, AstraZeneca&#8217;s programmed death ligand, or PD-L1, blocking antibody showed evidence of antitumor activity in people with advanced solid tumors and recurrent metastatic
        head and neck cancer.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Oncology/Other Clinical Pipeline</font></font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><img width="710" height="265" src="image07.jpg"></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Danvatirsen (formerly
          IONIS-STAT3-2.5</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">) &#8211; </font>Danvatirsen is a Generation 2.5 antisense medicine we designed
        to reduce the production of signal transducer and activator of transcription 3, or STAT3, to treat people with cancer. STAT3 is a protein involved in the translation of key factors critical for tumor cell growth and survival. STAT3 is over-active
        in a variety of cancers, including brain, lung, breast, bone, liver and multiple myeloma. Physicians believe that overactivity in STAT3 prevents cancer cell death and promotes tumor cell growth. Danvatirsen is a part of our collaboration with
        AstraZeneca to discover and develop anti-cancer medicines. We believe the significant potency we observed in our preclinical studies with danvatirsen broadens the therapeutic opportunities danvatirsen into many different types of cancer in which
        STAT3 is implicated.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In October 2018, we and AstraZeneca announced new data from a Phase 1b/2 study of danvatirsen in combination with
        durvalumab in recurrent metastatic head and neck cancer. The combination treatment resulted in seven percent of patients achieving a complete tumor response and 23 percent achieving either a partial or complete tumor response. This response rate is
        estimated to be double that with durvalumab alone, based on previous studies in this difficult to treat patient population. Results from this study demonstrated safety and tolerability profile supportive of continued development.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AstraZeneca is evaluating danvatirsen in a range of cancer types as part of a broader oncology partnership evaluating
        Generation 2.5 antisense therapies against undruggable targets either alone or in combination with immuno-oncology agents, including in non-small cell lung cancer, bladder cancer and head and neck cancer.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-AR-2.5</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211;</font> IONIS-AR-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, also known as AZD5312, is a Generation 2.5 antisense medicine we
        designed to treat people with prostate cancer by reducing the production of all known forms of androgen receptor, or AR, including variants of the AR gene. Prostate cancer is the second leading cause of cancer deaths in American men. Prostate
        cancer growth, proliferation and progression are all androgen-dependent and AR function is involved in disease progression at all stages of prostate cancer.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">An open-label, dose-escalation, Phase 1/2 clinical study of IONIS-AR-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> was completed in people with
        advanced tumors for which the androgen receptor pathway is potentially a contributing factor. The study was primarily conducted in prostate cancer patients and it showed durable responses in a number of those patients. The medicine exhibited a
        favorable safety and tolerability profile supportive of continued development. In March 2017, we licensed IONIS-AR-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to Ribo to develop and commercialize the medicine in China.</font></div>
    <div><br>
    </div>
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      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">16</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-HBV</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> and IONIS-HBV-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif; font-weight: bold;"> &#8211; </font>IONIS-HBV<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-HBV-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>are antisense
        medicines we designed to reduce the production of viral proteins associated with hepatitis B virus, or HBV. These include proteins associated with infection and replication, including the hepatitis B surface antigen, which is present in both acute
        and chronic infections and is associated with a poor prognosis in people with chronic HBV infection. IONIS-HBV-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> is our first anti-infective medicine in development that incorporates our LICA technology. Together with GSK, we are
        evaluating IONIS-HBV<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-HBV-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to treat HBV infection.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">HBV infection is a serious health problem that can lead to significant and potentially fatal health conditions,
        including cirrhosis, liver failure and liver cancer. Chronic HBV infection is one of the most common persistent viral infections in the world. Currently available therapies, although effective in reducing circulating HBV in the blood, do not
        effectively inhibit HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We and GSK are evaluating both IONIS-HBV<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-HBV-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in Phase 2 studies designed to reduce
        production of viral proteins associated with HBV infection.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>&#8211; <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> is a Generation 2+ LICA medicine we designed to reduce the production of complement factor B, or FB. FB is produced predominantly in the liver and circulates at high levels
          throughout the vascular system where it plays a pivotal role in an innate immunogenic cascade. Genetic association studies have shown that overactivity of this cascade has been associated with the development of several complement-mediated
          diseases, including dry age-related macular degeneration, or AMD.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In May 2017, we reported data from a randomized, placebo-controlled, dose-escalation Phase 1 study evaluating IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        in 54 healthy volunteers. Subjects treated with a single dose of IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> achieved dose-dependent reductions in plasma FB of up to 50 percent. Treatment with multiple doses of IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> during a six-week period resulted
        in greater reductions in circulating FB levels. In this study, IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> demonstrated a favorable safety and tolerability profile.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In October 2018, we entered into a new collaboration with Roche to develop IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for the treatment of
        complement-mediated diseases. The first indication that we and Roche agreed to pursue is the treatment of patients with geographic atrophy, or GA, the advanced stage of dry AMD. We plan to start a Phase 2 study of IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in people
        with dry AMD this year.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS-JBI1-2.5</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>is a Generation 2.5 antisense medicine we designed to treat people
        for an undisclosed target of gastrointestinal autoimmune disease. In December 2014, we entered into a collaboration agreement with Janssen to discover and develop antisense drugs that can be locally administered, including oral delivery, to treat
        autoimmune disorders of the GI tract. In July 2016, Janssen licensed IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>from us. Janssen is currently conducting a Phase 1 study of IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Preclinical Medicines in Development</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The efficiency and broad applicability of our technology enables us to develop medicines for a broad range of diseases.
        On average, it takes 12 to 18 months to complete the preclinical studies necessary to support clinical development. Over the last year we added eight new medicines to our preclinical pipeline.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Preclinical Pipeline</font></font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><img width="704" height="334" src="image08.jpg"></div>
    <div><br>
    </div>
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      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">17</font></div>
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Akcea Therapeutics: Our Affiliate Focused on Developing and Commercializing
        Medicines to Treat People with Serious and Rare Diseases</font></div>
    <div><br>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We formed Akcea Therapeutics in 2015 to focus on developing and commercializing medicines to treat people with serious
          and rare diseases. Akcea is commercializing TEGSEDI, a medicine we discovered and developed. Additionally, Akcea is advancing a mature pipeline of five of our novel medicines, including WAYLIVRA, AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>,
          AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, and AKCEA-TTR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, all with the potential to treat multiple diseases. We discovered all of these medicines, which are based on our proprietary antisense technology. Akcea is co-developing these five drugs
          with us.</font></div>
      <div><br>
      </div>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">This report includes financial information for this separate business segment in Note 7, <font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif; font-style: italic;">Segment Information and Concentration of Business Risk,</font> in the Notes to the Consolidated Financial Statements.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">TEGSEDI</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> &#8211; </font>See the medicine description under &#8220;Our Marketed Medicines&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; margin-left: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">WAYLIVRA &#8211;</font>See the
        medicine description under &#8220;WAYLIVRA &#8211; Potential Approval in Europe Following Positive CHMP</font></div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Opinion&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; See the medicine description under &#8220;Potential Next Wave of Pivotal Medicines&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-TTR-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; See the medicine description under &#8220;Potential Next Wave of Pivotal Medicines&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-ANGPTL3-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; See the medicine description under &#8220;Cardiometabolic and Renal Disease Pipeline&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;">Rx</font></sub> &#8211; See the medicine description under &#8220;Cardiometabolic and Renal Disease Pipeline&#8221; section above.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Satellite Company Medicines in Development</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have successfully developed novel medicines we designed to treat many different diseases. In therapeutic areas that
        are outside of our core areas of development, we have licensed our medicines to highly focused satellite companies that have the specific expertise and resources to continue developing the medicines. For our satellite company medicines, we refer to
        the medicine by the partner&#8217;s name or compound number, such as ZEMDRI or ATL1102. We have listed these medicines below in our Satellite Company pipeline.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Satellite Company Pipeline</font></font></div>
    <div><br>
    </div>
    <div style="text-align: center; text-indent: 35.3pt;"><img width="689" height="311" src="image09.jpg"></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:8d442353-6736-4e75-bf49-8b5789743f38">
    <div style="text-align: justify; text-indent: 35.3pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Antisense Technology</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our antisense technology is an innovative platform for discovering first-in-class and/or best-in-class medicines for
        treating disease. We believe this technology represents an important advance in the way we treat disease. Unlike most other drug technologies that work by affecting existing proteins in the body, antisense medicines target RNA, the intermediary
        that conveys genetic information from a gene to the protein synthesis machinery in the cell. By targeting RNA instead of proteins, we can use antisense technology to increase, decrease or alter the production of specific proteins. The unique
        properties of antisense technology provide several advantages over traditional drug discovery technologies.</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">These advantages include:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7cbba3a9c94c4b6a8453571d6a226719" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Direct intervention in the disease process at the genetic level by targeting RNA: antisense technology represents a direct route from gene to drug. The
                    explosion in genomic information and RNA biology has led to the discovery of many new disease-causing proteins and RNAs and has created new opportunities that are only accessible to antisense technology.</font></div>
              </td>
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        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z320792d6cd73437396c76cd77262d66b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z3cfc8da57e564763977781023227972f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Good drug properties: antisense medicines distribute well throughout the body without the need for special formulations or vehicles. They also have a
                    relatively long half-life of approximately two to four weeks in most tissues outside of the brain and spinal cord and three to four months in brain and spinal cord, which means patients and/or healthcare providers can dose our medicines
                    weekly, monthly or even less frequently depending on the medicine and target tissue.</font></div>
              </td>
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      <div>
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              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ability to combine with other drugs: because antisense medicines do not interact with the enzymes that metabolize or break down other drugs, physicians can
                    use our medicines in combination with other drugs.</font></div>
              </td>
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        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zc32a37eb380a4ae1bac96158bd47e94c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Broad applications to multiple disease targets, multiple tissues and multiple mechanisms: there are virtually no &#8220;undruggable&#8221; targets with antisense
                    technology.</font></div>
              </td>
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        </table>
      </div>
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    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z5906f46b40ed4dee8c2099c64c2d0155" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Utilize many different routes of administration including subcutaneous, intravenous, intrathecal, intravitreal, pulmonary and oral.</font></div>
              </td>
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    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zf8f023852d2647bfa99f063db5225c98" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Efficient discovery and early development: because of the efficiency of our antisense technology, our drug discovery and early development costs and success
                    rates compare favorably to small molecule or antibody drug discovery and development.</font></div>
              </td>
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        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We develop antisense medicines to potentially treat a wide range of diseases in a number of different therapeutic areas
        from severe and rare diseases to diseases that affect large patient populations. We focus our efforts on diseases in which there is a large unmet medical need with limited or no current treatments or in diseases for which we believe our medicines
        have a competitive advantage over existing therapies.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Technology Overview</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use our core technology platform to discover and develop medicines that affect targets in the body at the genetic
        level. Genes contain the information necessary to produce proteins. A gene is made up of nucleotides containing the nucleoside bases: adenine, thymine, guanine, and cytosine, commonly known as A, T, G and C, which are linked together to form a
        two-stranded structure that resembles a twisted ladder, known as deoxyribonucleic acid, or DNA. The nucleotides on one side of the ladder bind weakly to complementary nucleotides on the other strand according to specific rules; for example, A pairs
        with T and G pairs with C, creating the ladder&#8217;s rungs (Figure 1). Scientists call this highly specific nucleotide pairing hybridization. The sequence or order of these nucleotides establishes the cell&#8217;s recipes for making proteins. Each protein&#8217;s
        instructions reside in a corresponding segment of DNA known as a gene.</font></div>
    <div><br>
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      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">19</font></div>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Figure 1: Illustration of DNA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The instructions for making a protein are transcribed from a gene, or DNA into a different genetic molecule called
        messenger RNA. This process starts with the partial uncoiling of the two complementary strands of the DNA. One strand acts as a template and information stored in the DNA template strand is copied into a complementary RNA (Figure 2) by an enzyme
        called RNA polymerase, or RNAP. Messenger RNA, or mRNA, are mature, fully processed RNA that code for proteins.</font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Figure 2: Transcription of information contained in a gene, or DNA, to RNA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ribosomes, the cell&#8217;s factories for manufacturing proteins, translate mRNA into proteins. The ribosome reads the encoded
        information, the mRNA&#8217;s nucleotide sequence, and in doing so, strings together amino acids to form a specific protein (Figure 3).</font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><img width="716" height="252" src="image11.jpg"></div>
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      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">20</font></div>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Figure 3: Translation of the protein-coding information contained in mRNA to protein.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We primarily use our antisense technology to interrupt the cell&#8217;s protein production process by preventing the mRNA
        instructions from reaching the ribosome, thus inhibiting the production of the protein. We can also design antisense medicines to increase protein production for diseases caused by the lack of a particular protein or modify the processing (or
        splicing) of the mRNA, which can alter the composition of the protein. The mRNA sequence of nucleotides that carries the information for protein production is called the &#8216;sense&#8217; strand. Scientists call the complementary nucleotide chain that binds
        specifically to the sense strand the &#8220;antisense&#8221; strand. We use the information contained in mRNA to design chemical structures, that we call antisense oligonucleotides, or ASOs, or antisense medicines, which resemble DNA and RNA and are the
        complement of RNA. Our antisense medicines bind with high selectivity to the mRNA they were designed to target. Since each mRNA codes for a specific protein, this selectivity provides a level of specificity that is better than traditional drugs. As
        a result, we can design antisense medicines that selectively inhibit the disease-causing member of a protein family without interfering with other members of the protein family that might be necessary for normal cellular or bodily functions. This
        unique specificity means that antisense medicines may be less toxic than traditional drugs because we can design them to minimize the impact on unintended targets.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have developed the majority of the medicines in our pipeline using our advanced screens to produce medicines with
        what we believe have the best possible safety and tolerability profiles. We refer to our medicines that have passed these advanced screens as Generation 2+ medicines. We continue to advance our antisense technology to create even more potent
        medicines that we can use in more tissues and against more targets. These advances allow us to expand the mechanisms through which we can use our medicines. These advancements provide us with greater opportunities to use our antisense medicines to
        treat a greater number of diseases and reach more patient populations. Today several of our early stage medicines and those entering our pipeline use our most advanced antisense technology, including our next generation chemistries, Generation 2.5,
        and our LICA technology.</font></div>
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    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Generation 2.5 chemistry is an advancement that we have demonstrated increases the potency of our medicines by up to
        10-fold over our Generation 2+ medicines. This increase in potency enables our medicines to engage targets in a broader array of tissues. We have published data demonstrating that our Generation 2.5 medicines generally have enhanced potency over
        our Generation 2+ medicines and are broadly distributed throughout the body to multiple tissues including liver, kidney, lung, muscle, adipose, adrenal gland, peripheral nerves and tumor tissues. Our Generation 2.5 medicines constitute some of our
        recently added new medicines to our pipeline.</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">LICA is a chemical technology we developed that involves attaching a molecule called a ligand that binds with receptors
        on the surfaces of cells in a highly specific manner. Because these receptors are often found only on certain cell types, LICA allows us to increase effective delivery of our antisense medicines with higher specificity to certain cell types that
        express these receptors relative to non-conjugated antisense medicines. In November 2018, we published an integrated assessment of data from over 600 subjects, with more than 200 subjects on treatment for six months or longer, available from
        randomized placebo-controlled dose-ranging studies. The integrated assessment demonstrated with multiple Generation 2+ LICA medicines that our LICA technology for liver targets can increase potency by up to more than 30-fold over our non-LICA
        Generation 2+ medicines. In addition to the increase in potency, a favorable safety and tolerability profile was observed and was consistent across the entire LICA platform. There were no safety concerns related to platelets, liver or kidney
        function.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> further exemplifies these improvements. We designed this medicine to reduce the production of
        apolipoprotein(a), or Apo(a), protein in the liver to offer a direct approach for reducing lipoprotein(a), or Lp(a). The Phase 2 AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> study was the first and only medicine to selectively and robustly reduce Lp(a) levels below
        threshold levels associated with CVD in nearly all patients. This study included more than 280 patients, with 98 percent of patients in the high dose group achieving levels below 50 mg/dL, the recognized risk threshold for CVD. Like the integrated
        assessment, the safety and tolerability profile from this study was favorable and there were no safety concerns related to platelets, liver or kidney function.</font></div>
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    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have also combined our LICA technology with our Generation 2.5 chemistry medicines to further increase potency.
        Although we designed our first LICA medicines to inhibit targets in the liver, we are also developing LICA conjugation technology that we can use to target other tissues, such as the pancreas, and the initial results are promising.</font></div>
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    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Antisense Targets and Mechanisms</font></div>
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    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">There are more than a dozen different antisense mechanisms that we can exploit with our antisense technology. The
        majority of the medicines in our pipeline bind to mRNAs and inhibit the production of disease-causing proteins. However, our antisense technology is broadly applicable to many different antisense mechanisms, including modulation of RNA splicing,
        RNA interference, or RNAi, and enhancing protein translation to increase protein production. In May 2018, we published research showing that we can use our proprietary oligonucleotide technology with CRISPR/Cas9, a gene editing system that uses RNA
        to activate, target and edit specific sites on DNA. Our work in this area provides an important step toward developing potential therapeutic applications for CRISPR technology.</font></div>
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    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;When using antisense technology to inhibit the production of disease-causing proteins or reduce levels of harmful RNAs,
        our antisense medicines bind to the target RNA via highly specific nucleotide pairing, or hybridization, and recruit a cellular enzyme called ribonuclease H1, or RNase H1, to degrade the target RNA. The antisense medicine itself remains intact
        during this process, so it can remain active against additional target RNA molecules and repeatedly trigger their degradation (Figure 4). Examples of our antisense medicines that use the RNase H1 mechanism to reduce disease protein production
        include, WAYLIVRA, TEGSEDI, IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, IONIS-FXI-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx, </sub>AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, and others.</font></div>
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    <div style="text-align: center;"><img width="449" height="414" src="image13.jpg"></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Figure 4: Antisense medicine using the RNase H mechanism of action.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA is an example of an antisense medicine that modulates RNA splicing to increase protein production of the SMN
        protein (Figure 5), which is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular function. The SMN protein is deficient in people with SMA. There are a number of other diseases, including
        cystic fibrosis and Duchenne muscular dystrophy, which may be treated by modulating splicing using antisense technology.</font></div>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Figure 5: Antisense medicine altering splicing of the SMN2 mRNA.</font></div>
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    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Another class of RNA targets for our antisense technology are microRNAs. To date, scientists have identified more than
        700 microRNAs in the human genome, and have shown that the absence or presence of specific microRNAs in various cells is associated with specific human diseases, including cancer, viral infection, metabolic disorders and inflammatory disease. To
        fully exploit the therapeutic opportunities of targeting microRNAs, we co-founded Regulus Therapeutics as a company focused on the discovery, development and commercialization of microRNA-based therapeutics.</font></div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are also making progress in designing antisense medicines to target long, non-coding RNAs, or lncRNAs and RNAs that
        possess a toxic function in human diseases. Many of these RNAs, such as lncRNAs, do not make proteins but often cause disease by regulating the function of other genes or proteins. In 2014, we published a paper in <font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif; font-style: italic;">Nature</font> in which we were the first to show that targeted reduction of a lncRNA with an antisense compound can ameliorate certain cognitive deficits in a mouse model of
        Angelman syndrome, or AS. Moreover, these studies demonstrate the potential therapeutic benefits of antisense medicines for the treatment of AS.</font></div>
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    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Because the efficiency of our core technology platform can support multiple target-based antisense research programs
        without significantly increasing costs, we can develop antisense medicines to target a broad range of diseases, efficiently producing a large and broad proprietary portfolio of medicines. We are currently pursuing antisense drug discovery programs
        focused on various severe and rare diseases, cardiometabolic diseases, neurologic diseases, cancer and other diseases.</font></div>
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      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Partnering Strategy</font></div>
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      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have established alliances with a cadre of leading global pharmaceutical companies that are working alongside us in
          developing our medicines, advancing our technology, preparing to commercialize our medicines and selling our medicines. Our partners include the following companies, among others: AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis and Roche. Our
          partners bring resources and expertise that augment and build upon our internal capabilities. The depth of our knowledge and expertise with antisense technology together with our strong financial position provides us the flexibility to partner
          our medicines at what we believe is the optimal time to maximize the near-term, mid-term and long-term value of our medicines. We have distinct partnering strategies that we employ based on the specific program, therapeutic area and the expertise
          and resources our potential partners may bring to the collaboration.</font></div>
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                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have a strategic partnership with Biogen, which we expanded in 2018. Biogen provides expertise, tools and resources to complement our drug discovery
                      efforts. Our broad strategic alliance with Biogen pairs Biogen&#8217;s extensive resources and expertise in neurodegenerative diseases with our antisense technology. Together we are creating a franchise of novel medicines for
                      neurodegenerative diseases that has the potential to expand both our pipeline and Biogen&#8217;s pipeline with promising new medicines. Our development of and Biogen&#8217;s commercialization of SPINRAZA, is just one example of the power of our
                      strategic partnership.</font></div>
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                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have partnerships with companies that bring significant expertise and global
                        resources to develop and potentially commercialize medicines for a particular therapeutic area. For example, in January 2017, we initiated a collaboration with Novartis to develop and commercialize AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. In February 2019, Novartis licensed
                        AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>and we earned a $150 million license fee. Novartis is responsible for conducting and funding all future
                      development and commercialization activities for AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, including a global pivotal cardiovascular outcomes study, for which planning and initiation activities are underway.<font style="font-size: 10pt;
                        font-family: 'Times New Roman', Times, serif;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe Novartis brings significant resources and expertise to the collaboration that should
                        accelerate our ability to deliver these medicines to large patient populations who have high cardiovascular risk due to inadequately treated lipid disorders.</font></font></div>
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also form early stage research and development partnerships that allow us to expand the application of our technology to new therapeutic areas. For
                    example, we have a collaboration with Janssen that brings together our RNA-targeted technology platform and Janssen&#8217;s expertise in autoimmune disorders and therapeutic formulation to discover and develop antisense medicines to treat
                    autoimmune disorders in the GI tract. Thus far, Janssen has licensed and is advancing two medicines under our collaboration.</font></div>
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                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also work with a consortium of companies that can exploit our medicines and technologies outside our primary areas of focus. We refer to these companies
                      as satellite companies.</font></div>
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      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Financial Benefits of Our Partnerships</font></div>
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    <div style="text-align: justify; text-indent: 39.6pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Through our partnerships, we have earned both commercial revenue and a broad and sustaining base of R&amp;D revenue in
        the form of license fees, upfront payments and milestone payments. Since 2007, we have received more than $4 billion in cash from upfront and licensing fees, equity purchase payments, milestone payments, research and development funding and
        royalties from our partnerships. We have the potential to earn more than $20 billion in future milestone payments, licensing fees and other payments from our current partnerships, not including potential royalties.</font></div>
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    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Strategic Partnership</font></div>
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      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Biogen</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have several strategic collaborations with
          Biogen focused on using antisense technology to advance the treatment of neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen&#8217;s expertise in developing therapies for neurological
          disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with SMA. In</font> December 2017, we entered into a collaboration with Biogen to identify <font style="background-color: #FBFBFB; font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">new antisense medicines for the treatment of SMA</font>. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additionally, we and Biogen are currently developing six other
          medicines to treat neurodegenerative diseases under our other collaborations, including IONIS-SOD1</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for ALS, IONIS-MAPT</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">for Alzheimer&#8217;s disease</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">,</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> IONIS-C9</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub><font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">for ALS, and IONIS-BIIB6</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, IONIS-BIIB7</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;"> and IONIS-BIIB8</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> to treat undisclosed neurodegenerative diseases. In addition to these medicines, we
          and Biogen are evaluating numerous additional targets to develop medicines to treat neurological diseases. In April 2018, we entered into a new strategic collaboration for the treatment of neurological diseases with Biogen. From inception through
          February 2019, we have received over $2 billion from our Biogen collaborations, including $1 billion we received from Biogen in the second quarter of 2018 for our 2018 strategic neurology collaboration.</font></font></div>
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      <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Spinal Muscular Atrophy Collaborations</font></div>
      <div><br>
      </div>
      <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">SPINRAZA</font></div>
      <div><br>
      </div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2012, we entered into a
          collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA. Biogen reported in </font>January 2019 that SPINRAZA was approved in over 40 countries around the world. In February
        2019, SPINRAZA was approved in China. Biogen is responsible for global SPINRAZA commercial activities.</font></div>
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From inception through December 2018, we earned more than $785 million in total revenue under our SPINRAZA collaboration,
        including more than $350 million in revenue from SPINRAZA royalties and more than $435 million in R&amp;D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on any sales of SPINRAZA. We have exclusively in-licensed
        patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible
        for all further global development, regulatory and commercialization activities and costs for SPINRAZA.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">New antisense medicines for the treatment of SMA</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2017, we entered into a
          collaboration agreement with Biogen to </font>identify <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">new antisense medicines for the treatment of SMA</font><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">. </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Biogen will have the option to license therapies arising out of this collaboration
          following the completion of preclinical studies. Upon licensing, Biogen </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">will be responsible for all further global development, regulatory and commercialization
          activities and costs for such therapies</font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. Under the collaboration agreement, we received a </font>$25 million<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> upfront payment in December 2017. We will receive development and regulatory milestone payments from Biogen if new medicines advance towards
          marketing approval. </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In total over the term of our collaboration, we are eligible to receive up to $1.2 billion in license fees, milestone payments and other
          payments. In addition, we are eligible to receive tiered royalties </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">from the mid-teens to </font><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">mid-20 percent range </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">on net sales.</font><font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;">&#160;</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Neurology Collaborations</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">2018 Strategic Neurology</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In April 2018, we and Biogen entered into a
          new strategic collaboration to develop novel antisense medicines for a broad range of neurological diseases and entered into a Stock Purchase Agreement, or SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our
          antisense technology to develop therapies for these diseases for 10 years. We are responsible for the identification of antisense drug candidates based on selected targets</font>. Biogen is responsible for conducting IND-enabling toxicology
        studies for the selected target. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Biogen will have the option to license the selected target </font>after it completes the IND-enabling toxicology study. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If Biogen exercises its option for a medicine, it will assume </font>all <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">further global
          development, regulatory and commercialization responsibilities and costs for that medicine. </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the second quarter of 2018, we received
        </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$1 billion from Biogen, comprised of $</font>625<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million to purchase our stock at an
          approximately 25 percent cash premium and $375 million in an upfront payment. </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are eligible to receive up to $</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">270</font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> million in milestone payments for each medicine that
          achieves marketing approval. W</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">e have generated over $1 billion in payments through February 2019, including $15 million we received in the fourth quarter of 2018
          for advancing two targets under this collaboration. In addition, we are eligible to receive tiered royalties </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">up to the </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">20 percent range </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">on net sales.</font></font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">24</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">2013 Strategic Neurology</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In September 2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology
        to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines
        resulting from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen will have the option to license antisense medicines after Phase 2 proof of concept. In October 2016, we
        expanded our collaboration to include additional research activities we will perform. If Biogen exercises its option for a medicine, it will assume all further global development, regulatory and commercialization responsibilities and costs for that
        medicine. We are currently advancing five medicines, IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, IONIS-C9<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, IONIS-BIIB6<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, IONIS-BIIB7<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-BIIB8<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> under this collaboration. In December 2018, Biogen exercised its
        option to license IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, and as a result Biogen is now responsible for all further global development, regulatory and commercialization activities and costs for IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone
        payments, license fees and royalty payments for all medicines developed through this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug
        discovery and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee and milestone payments per program. We have generated over $215 million through February 2019, including $40 million we
        earned in the fourth quarter of 2018 when Biogen advanced and licensed IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any antisense medicines developed under this
        collaboration.</font></div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Neurology</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2012, we and Biogen entered into a collaboration agreement to develop and commercialize up to three novel
        antisense medicines to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine
        from each of the programs through the completion of the first Phase 2 study for each program. We are currently advancing IONIS-MAPT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for Alzheimer&#8217;s disease under this collaboration. If Biogen exercises its option for a medicine, it
        will assume all further global development, regulatory and commercialization responsibilities and costs for that medicine. Under the terms of the agreement, we received an upfront payment of $30 million. Over the term of the collaboration, we are
        eligible to receive up to $210 million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. We have generated over $55 million through February 2019. In addition, we are eligible to
        receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each program under the agreement.</font></div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For additional details about our collaboration agreements with Biogen, including other financial information and
          termination provisions, see Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements,</font> in the Notes to the Consolidated Financial
          Statements.</font></div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Research, Development and Commercialization Partners</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">AstraZeneca</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Cardiac, Renal and Metabolic Diseases Collaboration</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In July 2015, we and AstraZeneca formed a
          collaboration to discover and develop antisense therapies for treating cardiac, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed three medicines from us: IONIS-AZ4-2.5-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">, a medicine we designed to treat cardiovascular disease and our first </font>medicine that combines our Generation 2.5 and<font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif;"> LICA technology, IONIS-AZ5-2.5</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, a medicine we designed to </font>treat a genetically associated form of kidney disease and <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS-AZ6-2.5-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, a medicine we designed to </font>inhibit an undisclosed
        target to treat patients with NASH<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. AstraZeneca is responsible for all further global development, regulatory and commercialization activities and costs for each of the
          medicines it has licensed and any other future medicines AstraZeneca licenses.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of the agreement, we received a $65 million upfront payment. We are eligible to receive license fees and
        milestone payments of up to more than $4 billion as medicines under this collaboration advance. We have generated over $165 million in payments through February 2019, including a $10 million milestone payment we earned in the third quarter of 2018
        when AstraZeneca initiated a Phase 1 trial for IONIS-AZ4-2.5-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this
        collaboration agreement.</font></div>
    <div style="background-color: #FFFFFF;">
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      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Oncology Collaboration</font></div>
      <div><br>
      </div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2012, we entered into a
          collaboration agreement with AstraZeneca to discover and develop antisense medicines to treat cancer. As part of the agreement, we granted AstraZeneca an exclusive license to develop and commercialize </font>danvatirsen <font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">for the treatment of cancer. AstraZeneca is now responsible for all global development, regulatory and commercialization activities for </font>danvatirsen<font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">. We and AstraZeneca have evaluated </font>danvatirsen<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in people with head and neck cancer, advanced lymphoma and
          advanced metastatic hepatocellular carcinoma. AstraZeneca is evaluating </font>danvatirsen<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in combination with durvalumab, AstraZeneca&#8217;s PD-L1, blocking drug, in people
          with head and neck cancer, metastatic bladder cancer and metastatic non-small cell lung cancer. We and AstraZeneca also established an oncology research program. AstraZeneca has the option to license medicines resulting from the program, and if
          AstraZeneca exercises its option for a medicine, it will be responsible for all further global development, regulatory and commercialization activities and costs for such medicine. </font><font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;">In the fourth quarter of 2018, we added </font>IONIS-AZ7-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to our preclinical pipeline, a second drug under our oncology collaboration.</font></div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">25</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of this agreement, we
          received $31 million in upfront payments. We are eligible to receive milestone payments and license fees from AstraZeneca as programs advance in development. If AstraZeneca successfully develops </font>danvatirsen<font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;"> and another medicine under the research program, we could receive license fees and milestone payments of up to more than $450 million. We have generated over $125 million in payments through
          February 2019, including nearly $30 million in milestone payments we achieved when AstraZeneca advanced</font> danvatirsen and IONIS-AZ7-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, in the fourth quarter of 2018.<font style="font-size: 10pt; font-family: 'Times New Roman',
          Times, serif;"> In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any medicines resulting from these programs.</font></font></div>
    <div><br>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For additional details about our collaboration agreements with AstraZeneca, including other financial information and
          termination provisions, see Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements,</font> in the Notes to the Consolidated Financial
          Statements.</font></div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
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    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Bayer</font></div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
          for the prevention of thrombosis. We were responsible for completing a Phase 2 study of IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in people with end-stage renal disease on hemodialysis. Under the terms of the agreement, we received a $100 million upfront payment in
          the second quarter of 2015. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and to initiate development of IONIS-FXI-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, which Bayer licensed. In conjunction with the decision to advance these
          programs, we received a $75 million payment from Bayer. We are conducting a Phase 2b study evaluating IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in people with end-stage renal disease on hemodialysis to finalize dose selection. Additionally, we are developing
          IONIS-FXI-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> through Phase 1. Following these studies and Bayer&#8217;s decision to further advance these programs, Bayer will be responsible for all global development, regulatory and commercialization activities and costs for both
          medicines. We are eligible to receive additional milestone payments as each medicine advances toward the market. In total over the term of this collaboration, we are eligible to receive up to $385 million in license fees, milestone payments and
          other payments. We have generated over $175 million through February 2019. In addition, we are eligible to receive tiered royalties in the low to high 20 percent range on gross margins of both medicines combined.</font></div>
      <div><br>
      </div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For additional details about our collaboration agreement with Bayer, including other financial information and
          termination provisions, see Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements,</font> in the Notes to the Consolidated Financial
          Statements.</font></div>
      <div><br>
      </div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">GSK</font></div>
      <div><br>
      </div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In March 2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop
        new medicines against targets for rare and serious diseases, including infectious diseases and some conditions causing blindness. Under the terms of the agreement, we received upfront payments of $35 million. GSK is advancing two medicines
        targeting HBV under our collaboration: IONIS-HBV<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-HBV-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. GSK is currently conducting Phase 2 studies for both of these medicines, which we designed to reduce the production of viral proteins associated with HBV
        infection. GSK has the exclusive option to license the medicines resulting from this alliance at Phase 2 proof-of-concept for a license fee.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under our agreement, if GSK successfully develops these medicines and achieves pre-agreed sales targets, we could receive
        license fees and milestone payments of $262 million. We have generated over $162 million in payments through February 2019. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that GSK
        successfully commercializes under this alliance.</font></div>
    <div><br>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For additional details about our collaboration agreement with GSK, including other financial information and termination
          provisions, see Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements,</font> in the Notes to the Consolidated Financial Statements.</font></div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Janssen Biotech, Inc.</font></div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2014, we entered into a collaboration agreement with Janssen Biotech, Inc. to discover and develop antisense
          medicines that can be locally administered, including oral delivery, to treat autoimmune disorders of the GI tract. Janssen has the option to license medicines from us through the designation of development candidates for up to three programs.
          Under our collaboration, Janssen licensed IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in July 2016 and IONIS-JBI2-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in November 2017. Janssen is currently conducting a Phase 1 study of IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-JBI2-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> is
          in preclinical development. Prior to option exercise we are responsible for the discovery activities to identify development candidates. If Janssen exercises an option for any of the programs, it will be responsible for the global development,
          regulatory and commercial activities under that program. Under the terms of the agreement, we received $35 million in upfront payments. We are eligible to receive up to more than $800 million in <font style="font-size: 10pt; font-family: 'Times
            New Roman', Times, serif;">milestone payments and license fees </font>for these programs. We have generated over $75 million through February 2019. In addition, we are eligible to receive tiered royalties up to the near teens on net sales from
          any medicines resulting from this collaboration.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For additional details about our collaboration agreement with Janssen, including other financial information and
          termination provisions, see Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements,</font> in the Notes to the Consolidated Financial
          Statements.</font></div>
      <div><br>
      </div>
    </div>
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      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">26</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Roche</font></div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
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    <div style="text-align: left; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Huntington&#8217;s Disease</font></div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In April 2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to
          develop treatments for HD based on our antisense technology. Under the agreement, we discovered and developed IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, an antisense medicine targeting HTT protein, through completion of our Phase 1/2 clinical study in people with
          early stage HD. In December 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>and is now responsible for the global development, regulatory and commercialization activities for IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.
          Under the terms of the agreement, we received an upfront payment of $30 million in April 2013. We are eligible to receive up to $365 million in a license fee and milestone payments as IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> advances. We have generated over $145
          million through February 2019, including $35 million in milestone payments we generated in the first quarter of 2019 when Roche dosed the first patient in a Phase 3 study for IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. In addition, we are eligible to receive up to
          $136.5 million in milestone payments for each additional medicine successfully developed. We are also eligible to receive tiered royalties up to the mid-teens on net sales from any product resulting from this alliance.</font></div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times,
          serif;">IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="background-color: #FBFBFB;">Rx</font></sub><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for Complement-Mediated Diseases</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In October 2018, we entered into a
          collaboration agreement with Roche to</font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> develop IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;"> for the treatment of complement-mediated diseases. The first indication we plan to pursue is the treatment of patients with GA, the advanced stage of dry AMD. We are responsible for conducting a Phase 2 study in patients
          with dry AMD. In addition, we are exploring the medicine in a severe and rare renal indication. </font>Roche<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> has the option to license
          IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="background-color: #FBFBFB;">Rx</font></sub><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> at the completion of these studies. Upon licensing, </font>Roche





        <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">will be responsible for all further global development, regulatory and commercialization activities and costs.</font>&#160;<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of this agreement, we received a </font>$75 million<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;"> upfront payment in October 2018. We are eligible to receive up to </font>$684 million<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in milestone payments and
          license fees. In addition, we are also eligible to receive tiered royalties from the high teens to </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">twenty percent</font><font style="background-color: #FBFBFB;
          font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> on net sales.</font></font></div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For additional details about our collaboration agreements with Roche, including other financial information and
          termination provisions, see Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements,</font> in the Notes to the Consolidated Financial
          Statements.</font></div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Akcea Collaborations</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following collaboration agreements relate to Akcea, our majority-owned affiliate. Our consolidated results include all
        the revenue earned and cash received under these collaboration agreements. We reflect the noncontrolling interest attributable to other owners of Akcea&#8217;s common stock in a separate line on our statement of operations and in a separate line within
        stockholders&#8217; equity on our consolidated balance sheet.</font></div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Novartis</font></div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2017, we and Akcea initiated a collaboration with Novartis to develop and commercialize AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        and AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">&#160;</sub>Under the collaboration agreement, Novartis has an exclusive option to further develop and commercialize AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. Akcea is responsible for completing
        a Phase 2 program, conducting an end-of-Phase 2 meeting with the FDA and providing initial quantities of API for each medicine. If Novartis exercises an option for either of these medicines, Novartis will be responsible for all further global
        development, regulatory and co-commercialization activities and costs for such medicine.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea received a $75 million upfront payment in the first quarter of 2017. <font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;">In February 2019, Novartis licensed AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and we earned a $150 million license fee. Novartis is responsible for conducting and funding all future development, regulatory and
        commercialization activities for AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, including a global pivotal cardiovascular outcomes study, for which planning and initiation activities are underway.<font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif;">&#160;</font>If Novartis exercises its option for AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, Novartis will pay Akcea a license fee equal to $150 million. In addition, Akcea is eligible to receive up to $675 million and $530 million in milestone payments
        related to AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, respectively. Akcea is also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.
        Akcea will pay 50 percent of these license fees, milestone payments and royalties to us as a sublicense fee.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>In connection with Novartis&#8217; license of AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>,
        Akcea and Novartis established a more definitive framework under which the companies would negotiate the co-commercialization of AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in selected markets. Included in this framework is an option by which Novartis could solely
        commercialize AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in exchange for Novartis paying Akcea increased commercial milestone payments based on sales of AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea





          may co-commercialize IONIS-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> if licensed and commercialized by Novartis in selected markets through its specialized sales force under terms
          and conditions to be negotiated with Novartis in the future.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6
        million shares of our common stock for $100 million in the first quarter of 2017 and purchased $50 million of Akcea&#8217;s common stock at the IPO price concurrent with the IPO in July 2017.</font></div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For additional details about our collaboration agreement with Novartis, including other financial information and
          termination provisions, see Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements,</font> in the Notes to the Consolidated Financial
          Statements.</font></div>
      <div><br>
      </div>
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      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">27</font></div>
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    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">PTC Therapeutics</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In August 2018, Akcea entered into an exclusive license agreement with PTC Therapeutics to commercialize TEGSEDI and
        WAYLIVRA in Latin America. Under the license agreement, Akcea is eligible to receive up to $26 million in payments, including $12 million which it received in the third quarter of 2018, $6 million upon the earlier of FDA or EMA approval of WAYLIVRA
        and up to $8 million for regulatory milestones. Akcea is eligible to receive royalties from PTC in the mid-20 percent range on net sales in Latin America for each medicine. PTC&#8217;s obligation to pay Akcea royalties begins on the earlier of 12 months
        after the first commercial sale of a product in Brazil or the date that PTC recognizes revenue of at least $10 million in Latin America. Consistent with the agreements between Ionis and Akcea, the companies will share all payments, including
        royalties.</font></div>
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    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Satellite Company Partnerships</font></div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have a number of satellite company collaborations that expand the reach and potential of our RNA-targeting medicines
          into disease areas that are outside of our core focus.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, we have a collaboration with Alnylam Pharmaceuticals, Inc. to develop and commercialize RNAi therapeutics.
          Under the terms of the agreement, we exclusively licensed to Alnylam our patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics in exchange for a technology access fee,
          participation in fees from Alnylam&#8217;s partnering programs, as well as future milestone and royalty payments from Alnylam. We also have the potential to earn a portion of payments that Alnylam receives from licenses of our technology it grants to
          its partners, plus royalties. We retained rights to a limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate
          relating to antisense motifs and mechanisms and oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a
          license to develop and commercialize double-stranded RNAi drugs targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, In 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual
          property. Under this alliance, we and Alnylam each obtained exclusive license rights to four therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual
          property for oligonucleotides against four targets, including FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual
          property for oligonucleotides against four other targets. Alnylam also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we
          granted Alnylam a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In addition to Alnylam, our satellite company collaborations include collaborations with the following companies:</font></div>
      <div><br>
      </div>
    </div>
    <table cellspacing="0" cellpadding="0" id="zf2e420870ed44ea689615a9cb164d0fc" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 46.42%; vertical-align: top; border-bottom: #000000 2px solid;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Satellite Company</font></div>
          </td>
          <td style="width: 8.02%; vertical-align: top;">&#160;</td>
          <td style="width: 45.56%; vertical-align: top; border-bottom: #000000 2px solid;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Focus</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 46.42%; vertical-align: top;">
            <div style="background-color: #FFFFFF;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Achaogen, Inc.</font></div>
            </div>
          </td>
          <td style="width: 8.02%; vertical-align: top;">&#160;</td>
          <td style="width: 45.56%; vertical-align: top;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Aminoglycosides</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 46.42%; vertical-align: top;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense Therapeutics Limited</font></div>
          </td>
          <td style="width: 8.02%; vertical-align: top;">&#160;</td>
          <td style="width: 45.56%; vertical-align: top;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Inflammation, Acromegaly</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 46.42%; vertical-align: top;">
            <div style="background-color: #FFFFFF;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Atlantic Pharmaceuticals Limited</font></div>
            </div>
          </td>
          <td style="width: 8.02%; vertical-align: top;">&#160;</td>
          <td style="width: 45.56%; vertical-align: top;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Inflammation</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 46.42%; vertical-align: top;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dynacure, SAS</font></div>
          </td>
          <td style="width: 8.02%; vertical-align: top;">&#160;</td>
          <td style="width: 45.56%; vertical-align: top;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Muscle Disorders</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 46.42%; vertical-align: top;">
            <div style="background-color: #FFFFFF;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">ProQR Therapeutics N.V.</font></div>
            </div>
          </td>
          <td style="width: 8.02%; vertical-align: top;">&#160;</td>
          <td style="width: 45.56%; vertical-align: top;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ophthalmology</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 46.42%; vertical-align: top;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Regulus Therapeutics Inc.</font></div>
          </td>
          <td style="width: 8.02%; vertical-align: top;">&#160;</td>
          <td style="width: 45.56%; vertical-align: top;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">microRNA-targeting therapeutics</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 46.42%; vertical-align: top;">
            <div style="background-color: #FFFFFF;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Suzhou Ribo Life Science Co., Ltd.</font></div>
            </div>
          </td>
          <td style="width: 8.02%; vertical-align: top;">&#160;</td>
          <td style="width: 45.56%; vertical-align: top;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">ssRNAi</font></div>
          </td>
        </tr>

    </table>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under our satellite collaborations we are eligible to earn milestone payments, license fees and royalties. In addition, in
        certain cases we own equity in the company.</font></div>
    <div><br>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">External Project Funding</font></div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are pursuing discovery and development projects that provide us with new therapeutic applications for antisense
          medicines. These programs represent opportunities for us and our technology. In some cases, we have funded these studies through support from our partners or disease advocacy groups and foundations. Our External Project Funding partners include
          the following:</font></div>
      <div><br>
      </div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z27b9ac5f447f468f9149c4f3ab32c7ea" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"></td>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">CHDI Foundation</font><font style="font-size: 10pt;
                        font-family: 'Times New Roman', Times, serif;">- </font>Through our development collaboration, CHDI provided financial and scientific support to our Huntington&#8217;s disease drug discovery program. W<font style="font-size: 10pt;
                        font-family: 'Times New Roman', Times, serif;">e have reimbursed CHDI for its support of our Huntington&#8217;s disease program out of the payments we received from Roche.</font></font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z331a0c8ff0f648e88fc58fb09e08a62b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"></td>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Cystic Fibrosis Foundation</font>- We received upfront
                      funding from the Cystic Fibrosis Foundation to discover and advance a medicine for the treatment of cystic fibrosis. In exchange for this funding, we are obligated to pay the Cystic Fibrosis Foundation up to $18 million upon achieving
                      specific regulatory and sales events if we advance a medicine under our collaboration.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zda78d789b5ea4b40a79bf7e9462d3726" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"></td>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">The Ludwig Institute; Center for Neurological Studies- </font>We





                      have a collaboration with the Ludwig Institute, the Center for Neurological Studies and researchers to discover and develop antisense medicines for ALS and other neurodegenerative diseases. Under this agreement, we agreed to pay the
                      Ludwig Institute and the Center for Neurological Studies modest milestone payments and royalties on any antisense medicines resulting from the collaboration.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:95118b14-a353-4a44-8022-8c402c882e50">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">28</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Manufacturing</div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have dedicated significant resources to develop ways to improve manufacturing efficiency and capacity. Since we can use
        variants of the same nucleotide building blocks and the same type of equipment to produce our oligonucleotide medicines, we found that the same techniques we used to efficiently manufacture one oligonucleotide medicine could help improve the
        manufacturing processes for many other oligonucleotide medicines. By developing several proprietary chemical processes to scale up our manufacturing capabilities, we have greatly reduced the cost of producing oligonucleotide medicines. For example,
        we have significantly reduced the cost of raw materials through improved yield efficiency, while at the same time increasing our capacity to make the medicines. Through both our internal research and development programs and collaborations with
        outside vendors we may achieve even greater efficiency and further cost reductions.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our drug substance manufacturing facility is located in a 28,700 square foot building in Carlsbad, California. We
        purchased this building in 2017. In addition, we have a 25,800 square foot building that houses support functions for our manufacturing activities. We lease this facility under a lease that has an initial term ending in June 2021 with an option to
        extend the lease for up to two additional five-year periods. Our manufacturing facility is subject to periodic inspections by the FDA and foreign equivalents to ensure that it is operating in compliance with current Good Manufacturing Practices, or
        cGMP, requirements.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As part of our collaborations we may agree to manufacture clinical trial materials and/or commercial supply for our
        partners. For example, in the past we have manufactured clinical supply materials for AstraZeneca, Bayer, Biogen, GSK and Novartis.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe we have sufficient manufacturing capacity at our own facility or at contract manufacturing organizations, or
        CMOs, to meet our current internal research, development and potential commercial needs, as well as our current and future obligations under existing agreements with our partners for research, development and commercial needs. We believe our
        current network of CMO partners are capable of providing sufficient quantities to meet anticipated commercial demands. Additionally, we continue to evaluate relationships with additional suppliers to increase overall capacity and diversify our
        supply chain. While we believe that there are alternate sources of supply that can satisfy our commercial requirements, we cannot be certain that identifying and establishing relationships with such sources, if necessary, would not result in
        significant delay or material additional costs. We also cannot provide assurance that we will not experience a disruption in supply from our current CMO partners.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">CMOs are subject to the FDA&#8217;s cGMP requirements and other rules and regulations prescribed by foreign regulatory
        authorities. We depend on our CMO partners for continued compliance with cGMP requirements and applicable foreign standards.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Specifically, we have the following in place for our approved medicines, SPINRAZA and TEGSEDI, our medicine currently
        under regulatory review, WAYLIVRA and our medicine in Phase 3 development, IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">SPINRAZA</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Pursuant to our collaboration with Biogen, Biogen is responsible for SPINRAZA drug supply. We provided Biogen with API for
        SPINRAZA in 2018 under our manufacturing agreement with Biogen, which ended in September 2018. Biogen has an oligonucleotide synthesis manufacturing facility that gives it the capability to manufacture SPINRAZA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">TEGSEDI</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For TEGSEDI&#8217;s commercial drug supply, we are using CMOs to produce custom raw materials, API and finished goods. Our CMO
        partners have extensive technical expertise and cGMP experience.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">WAYLIVRA</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have supplied Akcea either through our manufacturing processes or through our outside vendors, with API and finished
        drug product to complete Akcea&#8217;s ongoing clinical study for WAYLIVRA. We have also supplied the API and the finished drug product for WAYLIVRA&#8217;s commercial launch. We believe we have sufficient API and drug product for at least the first two years
        of WAYLIVRA&#8217;s commercial launch. Akcea plans to leverage our relationships with CMOs to procure its own long-term raw material and drug supplies at competitive prices in the future.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">RX</sub></font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Pursuant to our collaboration with Roche, Roche is responsible for IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> drug supply.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">LICA Medicines</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have manufactured limited supplies of our LICA medicines for our preclinical and clinical studies. We have also used
        CMOs to manufacture our LICA medicines. LICA enables lower doses than unconjugated oligonucleotides. With our expertise in optimizing manufacturing of oligonucleotides, we believe we can develop new processes to scale up manufacturing of our LICA
        medicines at commercially competitive prices.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:64d58e2c-6783-4fd7-88c0-4645bc69d6a9">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">29</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    </div>
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Patents and Proprietary Rights</div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our success depends, in part, on our ability to obtain patent protection for our products in the U.S. and other countries.
        We own or have exclusively licensed a substantial patent estate with numerous issued patents worldwide protecting our products and, more generally, our platform for development and commercialization of oligonucleotide therapeutics. We focus our
        resources on patents and new patent applications that drive value for our company.</font></div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We own or control patents that provide exclusivity for products in our pipeline and patents that provide exclusivity for
        our core technology in the field of antisense more generally. Our core technology patents include claims to chemically modified nucleosides and oligonucleotides as well as antisense drug designs utilizing these chemically modified nucleosides.
        These core claims are each independent of specific therapeutic target, nucleic acid sequence, or clinical indication. We also own a large number of patents claiming antisense compounds having nucleic acid sequences complementary to therapeutic
        target nucleic acids, independent of the particular chemical modifications incorporated into the antisense compound. Most importantly, we seek and obtain issued patent claims to specifically protect each of our medicines. For example, we file and
        seek to obtain claims covering each drug&#8217;s nucleic acid sequence and precise drug design. In sum, we maintain our competitive advantage in the field of antisense technology by protecting our core platform technology and by creating multiple layers
        of patent protection for each of our specific medicines in development.</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zae99bd164ee84e728c8bc4190f3346fa" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 74.45%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Type of Patent Claim</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Broadly Applicable to Specific)</font></div>
          </td>
          <td style="width: 2.45%; vertical-align: top;">&#160;</td>
          <td style="width: 23.1%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 74.45%; vertical-align: top;">
            <div style="text-align: left; text-indent: -18pt; margin-left: 52.8pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font><font id="TRGRRTFtoHTMLTab" style="display: inline-block; text-indent: 0px; font-size:
                1px; width: 18pt;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Chemically Modified Nucleosides and Oligonucleotides (target and sequence independent)</font></div>
            <div style="text-align: left; text-indent: -18pt; margin-left: 52.8pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font><font id="TRGRRTFtoHTMLTab" style="display: inline-block; text-indent: 0px; font-size:
                1px; width: 18pt;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense Drug Design Motifs (target and sequence independent)</font></div>
            <div style="text-align: left; text-indent: -18pt; margin-left: 52.8pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font><font id="TRGRRTFtoHTMLTab" style="display: inline-block; text-indent: 0px; font-size:
                1px; width: 18pt;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Therapeutic Methods (sequence and chemistry independent)</font></div>
            <div style="text-align: left; text-indent: -18pt; margin-left: 52.8pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font><font id="TRGRRTFtoHTMLTab" style="display: inline-block; text-indent: 0px; font-size:
                1px; width: 18pt;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense Sequence (chemistry independent)</font></div>
            <div style="text-align: left; text-indent: -18pt; margin-left: 52.8pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font><font id="TRGRRTFtoHTMLTab" style="display: inline-block; text-indent: 0px; font-size:
                1px; width: 18pt;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Drug Composition</font></font></div>
            <div>&#160;</div>
          </td>
          <td style="width: 2.45%; vertical-align: top;">&#160;</td>
          <td style="width: 23.1%; vertical-align: top;">
            <div style="text-align: center;"><img width="115" height="129" src="image15.jpg"></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Chemically Modified Nucleosides and Oligonucleotides</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The most broadly applicable of our patents are those that claim modified nucleosides and oligonucleotides comprising the
        modified nucleosides that we incorporate into our antisense medicines to increase their therapeutic efficacy. Nucleosides and chemically modified nucleosides are the basic building blocks of our antisense medicines, therefore claims that cover any
        oligonucleotide incorporating one of our proprietary modified nucleosides can apply to a wide array of antisense mechanisms of action as well as several therapeutic targets. Of particular note are our patents covering our proprietary
        2&#8217;-O-(2-methoxy) ethyl, or &#8220;MOE,&#8221; modified nucleosides, incorporated into many of our second generation development compounds, as well as our constrained-ethyl nucleosides, or &#8220;cEt&#8221; nucleosides incorporated into our Generation 2.5 compounds.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following are some of our patents in this category in key jurisdictions (U.S., Europe and Japan):</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z2ce2539250e74951a355c367c9f7d4cc" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 9.97%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Jurisdiction</font></div>
          </td>
          <td style="width: 1.26%; vertical-align: bottom;">&#160;</td>
          <td style="width: 8.98%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Patent No.</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom;">&#160;</td>
          <td style="width: 30.92%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Title</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom;">&#160;</td>
          <td style="width: 8.98%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Expiration</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom;">&#160;</td>
          <td style="width: 36.9%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Description of Claims</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.97%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.26%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,101,993</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">OLIGONUCLEOTIDES CONTAINING 2&#8217;O-MODIFIED PURINES</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 36.9%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Covers certain MOE nucleosides and oligonucleotides containing these nucleotides.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.97%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.26%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,399,845</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.92%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 36.9%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Covers our cEt nucleosides and oligonucleotides containing these nucleoside analogs.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.97%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.26%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,741,457</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 36.9%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Covers our cEt nucleosides and oligonucleotides containing these nucleoside analogs.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.97%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.26%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,022,193</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.92%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 36.9%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Covers oligonucleotides containing cEt nucleoside analogs.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.97%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.26%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,569,686</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">COMPOUNDS AND METHODS FOR SYNTHESIS OF BICYCLIC NUCLEIC ACID ANALOGS</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 36.9%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Covers methods of synthesizing our cEt nucleosides.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.97%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Europe</font></div>
          </td>
          <td style="width: 1.26%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">EP1984381</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.92%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 36.9%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Covers our cEt nucleosides and oligonucleotides containing these nucleoside analogs.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.97%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Europe</font></div>
          </td>
          <td style="width: 1.26%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">EP2314594</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.92%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 36.9%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Covers our cEt oligonucleotides and methods of use.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.97%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Japan</font></div>
          </td>
          <td style="width: 1.26%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">JP5342881</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.92%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.98%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 36.9%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Covers our cEt nucleosides and oligonucleotides containing these nucleoside analogs.</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">30</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Antisense Drug Design Motifs</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also have patents that claim oligonucleotides comprising antisense drug design motifs, or patterns of nucleoside
        modifications at specified positions in the oligonucleotide. Patent claims covering our antisense drug design motifs are independent of nucleic acid sequence, so they cover oligonucleotides having the recited motif, regardless of cellular target or
        clinical indication. The claimed motifs generally confer properties that optimize oligonucleotides for a particular antisense mechanism of action, such as ribonuclease H, or RNase H, RNAi, or splicing. We have designed oligonucleotides
        incorporating motifs, which we refer to as chimeric compounds or gapmers, to exploit the RNase H mechanism to achieve target RNA reduction. Almost all of our medicines, including TEGSEDI, WAYLIVRA and IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, but excluding SPINRAZA,
        contain this gapmer antisense drug design motif. We own a U.S. patent that covers all of our second generation MOE gapmer antisense medicines until March of 2023.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In addition, we have pursued patent claims to antisense drug design motifs incorporating bicyclic nucleoside analogs,
        which include both locked nucleic acids, or &#8220;LNA&#8221; and cEt. In Europe, we have been granted claims drawn to certain short gapmer oligonucleotides with bicyclic nucleosides, which include locked nucleic acids, in the wings for the treatment of
        cardiovascular or metabolic disorders. We have also successfully obtained issued patent claims covering our Generation 2.5 gapmer antisense drug design motifs that incorporate our cEt modified nucleosides. Santaris opposed granted European patents
        EP2092065 and EP2410053. In April 2015, the claims of EP2092065 were successfully upheld in amended form and in January 2017, EP2410053 was upheld with only a minor amendment. The following patents are some examples of our issued patents in this
        category in key jurisdictions:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z6220656702b8404baf47d5646c24c767" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Jurisdiction</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Patent/</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Application No.</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Title</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Expiration</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Description of Claims</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,015,315</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">GAPPED OLIGONUCLEOTIDES</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2&#8217;-O-alkyl-O-alkyl gapmer oligonucleotides.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Europe</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">EP2021472</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">COMPOUNDS AND METHODS FOR MODULATING GENE EXPRESSION</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Short gapmer oligonucleotides, having wings of 2 bicyclic nucleosides, and a gap of 10 deoxynucleotides for the treatment of
                cardiovascular or metabolic disorders</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,750,131</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5&#8217;-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5&#8217;-Methy BNA containing gapmer compounds</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Europe</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">EP2092065</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">ANTISENSE COMPOUNDS</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Gapmer compounds having wings comprised of 2&#8217;-modifed and LNA nucleosides</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Europe</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">EP2410053</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">ANTISENSE COMPOUNDS</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Gapmer compounds having wings comprised of 2&#8217;-MOE and bicyclic nucleosides</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Japan</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">JP 5665317</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">ANTISENSE COMPOUNDS</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Gapmer compounds having wings comprised of 2&#8217;-MOE and bicyclic nucleosides</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Europe</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">EP2673361</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">OLIGOMERIC COMPOUNDS COMPRISING BICYCLIC NUCLEOTIDES AND USES THEREOF</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2032</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Gapmer having at least one bicyclic nucleoside, 2&#8217;-modified nucleoside, and 2&#8217;-deoxynucleoside in either the 5&#8217;- or 3&#8217;-wing.</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">LIgand-Conjugated Antisense (LICA) Technology</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have also pursued patent claims to new chemistries created to enhance targeting of antisense medicines to specific
        tissues and cells to improve a drug&#8217;s properties. We designed our N-acetyl-galactosamine, or GalNAc, LICA medicines to provide an increase in potency for targets in the liver. We have successfully obtained issued patent claims covering our LICA
        technology conjugated to any modified oligonucleotide, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides. The following patents are some examples of our issued patents in this category:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z5cdfd52e921d4bc6a1c29ccf72cbb3c2" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 9.67%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Jurisdiction</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Patent/</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Application No.</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Title</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Expiration</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Description of Claims</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,127,276</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2034</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Covers our primary THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully
                modified oligonucleotides</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,181,549</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2034</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Covers our primary THA conjugate having our preferred linker and cleavable moiety conjugated to any oligomeric compound or any
                nucleoside having a 2&#8217;-MOE modification or a cEt modification</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Therapeutic Methods of Treatment and Antisense Drug Sequences</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In addition to our broad core patents, we also own hundreds of patents, worldwide, with claims to antisense compounds
        having particular sequences and compounds directed to particular therapeutically important targets or methods of achieving clinical endpoints using these antisense compounds. These &#8220;Target&#8221; patents also include claims reciting the specific nucleic
        acid sequences utilized by our products, independent of chemical modifications and motifs. In addition, our product specific patents typically include claims combining specific nucleic acid sequences with nucleoside modifications and motifs. In
        this way, we seek patent claims narrowly tailored to protect our product&#8217;s specifically, in addition to the broader core antisense patents described above.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">31</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">SPINRAZA and Survival Motor
          Neuron</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA is protected from generic competition in the U.S. until at least 2030 and in Europe until 2026 by a suite of
        patents. These issued patents include: (i) the Bennett patent related to methods of altering mRNA processing (e.g., splicing, the mechanism of action of SPINRAZA) with a fully modified 2&#8217;MOE oligonucleotide, (ii) a patent licensed from the
        University of Massachusetts drawn to antisense compounds having the sequence of SPINRAZA, independent of chemical modification and uses of such compounds for treating SMA, and (iii) joint patents with Cold Spring Harbor Laboratory claiming fully
        modified 2&#8217;MOE compositions targeting SMN2, including the precise composition of matter of SPINRAZA and methods of using such compositions. We have filed for patent term extension, to potentially extend the term beyond 2030. With Biogen&#8217;s license
        of SPINRAZA, we assigned our interest in these patents to Biogen. The table below lists the key U.S. and European issued patents protecting SPINRAZA:</font></div>
    <div><br>
    </div>
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        <tr>
          <td style="width: 9.67%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Jurisdiction</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Patent No.</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Title</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Expiration</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Description of Claims</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,361,977</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2030</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Sequence and chemistry (full 2&#8217;-MOE) of SPINRAZA</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Europe</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1910395</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2026</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Sequence and chemistry (full 2&#8217;-MOE) of SPINRAZA</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,838,657</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Oligonucleotides having sequence of SPINRAZA (chemistry independent)</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,110,560</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2025</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Methods of using antisense oligonucleotides having sequence of SPINRAZA to alter splicing of SMN2 and/or to treat SMA</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,980,853</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2030</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Methods of administering SPINRAZA</font></div>
          </td>
        </tr>

    </table>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"></font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">TEGSEDI and Transthyretin</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We obtained issued claims covering TEGSEDI in the U.S. The issued U.S. claims protect TEGSEDI from generic competition in
        the U.S. until at least 2031. We are also pursuing additional patent applications designed to protect TEGSEDI in foreign jurisdictions. The table below lists the current issued patents protecting TEGSEDI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">&#160;</sub>in key jurisdictions:</font></div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zbb67a5f3a02a481eb2b11f85bcd5a940" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 9.67%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Jurisdiction</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>
          <td style="width: 8.79%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Patent No.</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>
          <td style="width: 30.07%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Title</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>
          <td style="width: 8.81%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Expiration</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>
          <td style="width: 36%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Description of Claims</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,101,743</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.07%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF TRANSTHYRETIN EXPRESSION</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2025</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 36%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense sequence and chemistry of TEGSEDI</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,697,860</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.07%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">DIAGNOSIS AND TREATMENT OF DISEASE</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.81%; vertical-align: top; background-color: #FFFFFF;">
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          </td>
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          <td style="width: 36%; vertical-align: top; background-color: #FFFFFF;">
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          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
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          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Japan</font></div>
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          <td style="width: 36%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
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          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">EP2563920</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF TRANSTHYRETIN EXPRESSION</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
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          <td style="width: 36%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Composition of TEGSEDI</font></div>
          </td>
        </tr>

    </table>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">WAYLIVRA and Apolipoprotein C-III</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have obtained patent claims in the U.S. drawn to the use of antisense compounds complementary to a broad active region
        of human Apo C-III, including the site targeted by WAYLIVRA. We have secured similar claims to compounds complementary to any site on human Apo C-III in Australia. We have also obtained issued patent claims to the specific antisense sequence and
        chemical composition of WAYLIVRA in the U.S., Australia, Canada, Hong Kong and Europe. The issued U.S. claims protect WAYLIVRA from generic competition in the U.S. until at least 2023. In addition, if WAYLIVRA is approved by the FDA, we will seek
        patent term extension to recapture a portion of the term lost during FDA regulatory review, extending the term of this patent beyond 2023. We are pursuing additional patent applications designed to protect WAYLIVRA worldwide. The table below lists
        the issued patents in key jurisdictions:</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">32</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div><br>
    </div>
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        <tr>
          <td style="width: 9.67%; vertical-align: bottom; background-color: #FFFFFF;">
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          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Patent No.</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Title</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Expiration</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Description of Claims</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF APOLIPOPROTEIN C-III EXPRESSION</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense compound specifically hybridizable within the nucleotide region of apoCIII targeted by WAYLIVRA</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,598,227</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF APOLIPOPROTEIN C-III EXPRESSION</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div>
          </td>
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          <td style="width: 35.94%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Methods of treating hyperlipidemia, lowering cholesterol levels or lowering triglyceride levels with WAYLIVRA</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
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          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,750,141</font></div>
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          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense sequence and chemistry of WAYLIVRA</font></div>
            <div>&#160;</div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Europe</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">EP1622597</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF APOLIPOPROTEIN C-III EXPRESSION</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2024</font></div>
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          <td style="width: 35.94%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense sequence and chemistry of WAYLIVRA</font></div>
          </td>
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          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Europe</font></div>
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          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
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          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF APOLIPOPROTEIN C-III EXPRESSION</font></div>
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          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2024</font></div>
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          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense compound specifically hybridizable within the nucleotide region of apoCIII targeted by WAYLIVRA</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,157,082</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF APOLIPOPROTEIN CIII (APOCIII) EXPRESSION</font></div>
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          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2032</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Methods of using APOCIII antisense oligonucleotides for reducing pancreatitis and chylomicronemia and increasing HDL</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Japan</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF APOLIPOPROTEIN CIII (APOCIII) EXPRESSION</font></div>
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          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2032</font></div>
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          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Methods of using APOCIII antisense oligonucleotides having the sequence of WAYLIVRA for treating pancreatitis</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
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          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
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          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2034</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 35.94%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Methods of using APOCIII specific inhibitors for treating lipoprotein lipase deficiency</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and Huntingtin</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We obtained issued claims covering IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in the U.S.. The issued U.S. claims protect IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        from generic competition in the U.S. until at least 2030. We are also pursuing additional patent applications designed to protect IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in foreign jurisdictions. The table below lists the current issued patents protecting IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx





        </sub>in key jurisdictions:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z7ceb11ab992a40da947326a7eeab3d8e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 9.67%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Jurisdiction</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>
          <td style="width: 8.79%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Patent No.</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>
          <td style="width: 30.07%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Title</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>
          <td style="width: 8.81%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Expiration</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom;">&#160;</td>
          <td style="width: 36%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Description of Claims</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,273,315</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.07%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF HUNTINGTIN EXPRESSION</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2030</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 36%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Composition of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,906,873</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.07%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF HUNTINGTIN EXPRESSION</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.81%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2030</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 36%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Methods of treating Huntington&#8217;s disease by administering IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Europe</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">EP2475675</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.07%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF HUNTINGTIN EXPRESSION</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2030</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 36%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Composition of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Japan</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">JP5809146</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.07%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">MODULATION OF HUNTINGTIN EXPRESSION</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.81%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2030</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 36%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Composition of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,951,934</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.07%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">COMPOSITIONS AND THEIR USES DIRECTED TO HUNTINGTIN</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 36%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense sequence of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,952,145</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.07%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">COMPOSITIONS AND THEIR USES DIRECTED TO HUNTINGTIN</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.81%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 36%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense compound specifically hybridizable within the nucleotide region of HTT targeted by IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Japan</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5425474</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 30.07%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">COMPOSITIONS AND THEIR USES DIRECTED TO HUNTINGTIN</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 8.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 36%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense sequence of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 9.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">European</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.79%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">EP2161038</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 30.07%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">COMPOSITIONS AND THEIR USES DIRECTED TO HUNTINGTIN</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 8.81%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2027</font></div>
          </td>
          <td style="width: 1.67%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 36%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense sequence of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub></font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We seek patent protection in significant markets and/or countries for each medicine in development. We also seek to
        maximize patent term. In some cases, the patent term can be extended to recapture a portion of the term lost during FDA regulatory review. The patent exclusivity period for a medicine will prevent generic medicines from entering the market. Patent
        exclusivity depends on a number of factors including initial patent term and available patent term extensions based upon delays caused by the regulatory approval process.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">33</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Manufacturing Patents</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also own patents claiming methods of manufacturing and purifying oligonucleotides. These patents claim methods for
        improving oligonucleotide drug manufacturing, including processes for large-scale oligonucleotide synthesis and purification. These methods allow us to manufacture oligonucleotides at lower cost by, for example, eliminating expensive manufacturing
        steps.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also rely on trade secrets, proprietary know-how and continuing technological innovation to develop and maintain a
        competitive position in antisense therapeutics.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:5380c5da-7bec-4337-a256-d389ed787692">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Government Regulation</div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 35pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Regulation by government authorities in the U.S. and other countries is a significant component in the development,
        manufacture and commercialization of pharmaceutical products and services. In addition to regulations enforced by the FDA and relevant foreign regulatory authorities, we are also subject to regulation under the Occupational Safety and Health Act,
        the Environmental Protection Act, the Toxic Substances Control Act, the Resource Conservation and Recovery Act and other present and potential future federal, state and local regulations.</font></div>
    <div style="text-align: justify; text-indent: 35pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Extensive regulation by the U.S. and foreign governmental authorities governs the development, manufacture and sale of our
        medicines. In particular, our medicines are subject to a number of approval requirements by the FDA in the U.S. under the Federal Food, Drug and Cosmetic Act, or FDCA, and other laws and by comparable agencies in those foreign countries in which we
        conduct business. The FDCA and other various federal, state and foreign statutes govern or influence the research, testing, manufacture, safety, labeling, storage, recordkeeping, approval, promotion, marketing, distribution, post-approval
        monitoring and reporting, sampling, quality, and import and export of our medicines. State, local, and other authorities also regulate pharmaceutical manufacturing facilities and procedures.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;Our manufacturing facility and our CMOs are subject to periodic inspection by the FDA and other foreign equivalents to
        ensure that they are operating in compliance with cGMP requirements. In addition, marketing authorization for each new medicine may require a rigorous manufacturing pre-approval inspection by regulatory authorities. Post approval, there are strict
        regulations regarding changes to the manufacturing process, and, depending on the significance of the change, changes may require prior FDA approval. FDA regulations also require investigation and correction of any deviations from cGMP and impose
        reporting and documentation requirements upon us and any third-party manufacturers that we may decide to use.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The FDA must approve any new medicine before a manufacturer can market it in the U.S.. In order to obtain approval, we and
        our partners must complete clinical studies and prepare and submit an NDA to the FDA. If the FDA approves a medicine, it will issue an approval letter authorizing commercial marketing of the medicine and may require a risk evaluation and mitigation
        strategy, or REMS, to help ensure the benefits of the medicine outweigh the potential risks. For example, TEGSEDI has a REMS program. The requirements for REMS can materially affect the potential market and profitability of our medicines. In
        foreign jurisdictions, the drug approval process is similarly demanding.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Numerous regulatory authorities in addition to the FDA, including, in the U.S., the Centers for Medicare &amp; Medicaid
        Services, other divisions of the U.S. Department of Health and Human Services, the U.S. Department of Justice, and similar foreign, state and local government authorities, regulate sales, promotion and other activities following drug approval. Only
        those claims relating to safety and efficacy that the FDA has approved may be used in labeling. We are only allowed to use promotional communications regarding a drug that are consistent with the information in the drug&#8217;s approved labeling. The FDA
        and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For any approved medicine, domestic and foreign sales of the medicine depend, in part, on the availability and amount of
        reimbursement by third party payors, including governments and private health plans. Private health plans may seek to manage cost and use of our medicines by implementing coverage and reimbursement limitations. Governments may also regulate or
        influence coverage, reimbursement and/or pricing of our medicines to control cost or affect use. Within the EU a variety of payors pay for medicines, with governments being the primary source of payment. Negotiating pricing with governmental
        authorities can delay commercialization. Such pricing and reimbursement factors could impact our ability, including Akcea, and that of our commercial partners to successfully commercialize approved medicines.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the U.S. and foreign jurisdictions, the legislative landscape continues to evolve. There have been a number of
        legislative and regulatory changes to the healthcare system that could affect our future results of operations. In particular, there have been and continue to be a number of initiatives at the U.S. federal and state levels and by foreign
        governments that seek to reduce healthcare costs. There has also been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in efforts to bring more transparency to drug
        pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for medicines.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other healthcare laws that may affect our ability to operate include the federal Health Insurance Portability and
        Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected
        health information; analogous foreign and state laws governing the privacy and security of health information, such as the General Data Protection Regulation, or GDPR, in the EU, and the California Consumer Privacy Act, or CCPA, in California, some
        of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect; and the Physician Payments Sunshine Act, which requires manufacturers of medicines, devices, biologics, and
        medical supplies to report annually to the U.S. Department of Health and Human Services information related to payments and other transfers of value to physicians and teaching hospitals, and ownership and investment interests held by physicians and
        their immediate family members.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">34</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our operations may be directly, or indirectly through our customers, distributors, or other business partners, subject to
        various federal and state fraud and abuse laws, including, without limitation, anti-kickback statutes and false claims statutes. These laws may impact, among other things, our, Akcea&#8217;s, and our partners&#8217; proposed sales, marketing and education
        programs.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The U.S. Foreign Corrupt Practices Act, or FCPA, prohibits certain individuals and entities, including us, from promising,
        paying, offering to pay, or authorizing the payment of anything of value to any foreign government official, directly or indirectly, to obtain or retain business or an improper advantage. If we violate the FCPA, it could result in large civil and
        criminal penalties as well as an adverse effect on our reputation, operations, and financial condition. We could also face collateral consequences such as debarment and the loss of export privileges.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:d6c46e32-e4b7-44d5-ae77-76bb4f9fb34b">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Competition</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 39.6pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Our Business in General</font></div>
    <div style="text-align: justify; text-indent: 39.6pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Some of our medicines may compete with existing therapies for market share. In addition, there are a number of companies
        pursuing the development of oligonucleotide-based technologies and the development of pharmaceuticals utilizing these technologies. These companies include specialized pharmaceutical firms and large pharmaceutical companies acting either
        independently or together with biopharmaceutical companies. Our medicines are differentiated from traditional small molecule medicines by their chemistry, how they move in the body, how they act in the body, delivery technology, and formulations.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our approved products and our products under development address numerous markets. The diseases our medicines target for
        which we have or may receive marketing authorization will determine our competition. For some of our products, an important factor may be the timing of market introduction of competitive products. Accordingly, the relative speed with which we can
        develop products, complete the clinical trials and marketing authorization processes and supply commercial quantities of the products to the market are important competitive factors. We expect to compete among products approved for sale based on a
        variety of factors, including, among other things, product efficacy, safety, mechanism of action, dosing convenience, marketing and sales strategy and tactics, availability, price, and reimbursement.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Below we have included what we believe to be the competitive landscape for the following key programs:</font></div>
    <div><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z0218333ab03148acb2ae844d5f0a5e73" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Marketed Medicines: SPINRAZA and TEGSEDI</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zc75ab04b88ef4d079e1c33bd393ba09f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Medicine under regulatory review: WAYLIVRA</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zec1239803db944d8a9ee68e8488fc8f6" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Medicine currently in pivotal trials: IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub></font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Marketed Medicines</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">SPINRAZA</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe that the following medicines could compete with SPINRAZA:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z09160f2cc8214b76b770da258e8bbc5f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 12.38%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine</font></div>
          </td>
          <td style="width: 10.89%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Company</font></div>
          </td>
          <td style="width: 12.59%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine Description</font></div>
          </td>
          <td style="width: 8.43%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Phase</font></div>
          </td>
          <td style="width: 11.69%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Admin/Dosing</font></div>
          </td>
          <td style="width: 22.27%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Efficacy(1)</font></div>
          </td>
          <td style="width: 21.75%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Safety(1)</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 12.38%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Zolgensma</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(AVXS-101)</font></div>
          </td>
          <td style="width: 10.89%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Novartis</font></div>
          </td>
          <td style="width: 12.59%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Gene therapy that corrects the SMN1 gene using the</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AAV9 Vector</font></div>
          </td>
          <td style="width: 8.43%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under FDA Review</font></div>
          </td>
          <td style="width: 11.69%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Infusion</font></div>
          </td>
          <td style="width: 22.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Demonstrated an increase in survival and improvement in achievement of developmental milestones vs the natural history of SMA Type 1.
                Study included a small number of patients.</font></div>
          </td>
          <td style="width: 21.75%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Generally well tolerated to date and the most commonly observed side effect was elevated liver enzymes. Study included a small number
                of patients.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 12.38%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Risdiplam</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(RG7916)</font></div>
            <div>&#160;</div>
          </td>
          <td style="width: 10.89%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">PTC Therapeutics/ Roche/ SMA Foundation</font></div>
            <div>&#160;</div>
          </td>
          <td style="width: 12.59%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A small molecule drug that modulates splicing of the</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SMN2 gene</font></div>
          </td>
          <td style="width: 8.43%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td style="width: 11.69%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Oral</font></div>
          </td>
          <td style="width: 22.27%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Preliminary findings from Part 1 of the FIREFISH study show that infants with Type 1 SMA are meeting developmental milestones
                including sitting without support.</font></div>
            <div>&#160;</div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Preliminary findings from Part 1 of the SUNFISH study show improvements in motor function in people with Type 2/3 SMA.</font></div>
            <div>&#160;</div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Studies included a small number of patients.</font></div>
            <div>&#160;</div>
          </td>
          <td style="width: 21.75%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Safe and well tolerated at all doses and had no drug-related or safety-related study withdrawals. Studies included a small number of
                patients.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 12.38%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Reldesemtiv</font></div>
          </td>
          <td style="width: 10.89%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cytokinetics/<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><br>
                </font>Astellas</font></div>
          </td>
          <td style="width: 12.59%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A selective, fast skeletal muscle troponin activator</font></div>
          </td>
          <td style="width: 8.43%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td style="width: 11.69%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Oral</font></div>
          </td>
          <td style="width: 22.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The Phase 2 study demonstrated dose-dependent increases in six minute walk distance in ambulatory patients as measured at both
                post-baseline time points, week four and week eight</font></div>
          </td>
          <td style="width: 21.75%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Adverse events were similar between groups receiving reldesemtiv and placebo. The most commonly observed adverse effects were
                headache, constipation and nausea</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 12.38%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Firdapse</font></div>
          </td>
          <td style="width: 10.89%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Catalyst/Jazz/</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">BioMarin</font></div>
          </td>
          <td style="width: 12.59%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A potassium channel blocker that increases the release of acetylcholine</font></div>
          </td>
          <td style="width: 8.43%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td style="width: 11.69%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Oral</font></div>
          </td>
          <td style="width: 22.27%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">None reported</font></div>
          </td>
          <td style="width: 21.75%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">None reported</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zb1e2c725d39244f1b405d73e5d47a3be" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Taken from public documents including respective company press releases, company presentations, and scientific presentations.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">35</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe that Zolgensma, if approved, may be the first medicine to compete with SPINRAZA. The FDA accepted Novartis&#8217;
        biologics licensing application, or BLA, for Zolgensma, in December 2018 and regulatory action is anticipated in May 2019. The filing is supported by data from the START trial, which demonstrated an increase in survival and improvement in
        achievement of developmental milestones compared to the natural history of SMA Type 1. The START trial included 15 patients.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">TEGSEDI</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe that the following medicines could compete with TEGSEDI:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z040060ef9bb14ffda6544d3e64498cb3" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 11.14%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine</font></div>
          </td>
          <td style="width: 10.44%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Company</font></div>
          </td>
          <td style="width: 15.35%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine Description</font></div>
          </td>
          <td style="width: 14.99%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Phase</font></div>
          </td>
          <td style="width: 11.35%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Admin/Dosing</font></div>
          </td>
          <td style="width: 16.11%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Efficacy(1)</font></div>
          </td>
          <td style="width: 20.62%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Safety(1)</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 11.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Onpattro</font></div>
          </td>
          <td style="width: 10.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Alnylam</font></div>
          </td>
          <td style="width: 15.35%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">An RNAi drug formulated with lipid nanoparticles to inhibit TTR mRNA</font></div>
          </td>
          <td style="width: 14.99%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Approved</font></div>
          </td>
          <td style="width: 11.35%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Infusion every 3 weeks with pre-treatment with steroids</font></div>
          </td>
          <td style="width: 16.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84.3% mean reduction in TTR at 18 months</font></div>
          </td>
          <td style="width: 20.62%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Most common AEs more frequently observed in Onpattro arm vs. placebo were peripheral edema (29.7% vs.</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22.1%) and infusion-related reactions (18.9% vs. 9.1%)</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 11.14%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Tafamidis</font></div>
          </td>
          <td style="width: 10.44%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Pfizer</font></div>
          </td>
          <td style="width: 15.35%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A small molecule drug to stabilize TTR Protein</font></div>
          </td>
          <td style="width: 14.99%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercially available in the EU for stage 1 hATTR amyloidosis with polyneuropathy. Under review in the U.S. for ATTR with
                cariodmyopathy with a PDUFA date in July 2019</font></div>
          </td>
          <td style="width: 11.35%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Daily oral capsule</font></div>
          </td>
          <td style="width: 16.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In 45% of patients taking Tafamidis, nerve function either improved or stabilized, compared with 30% of patients taking placebo</font></div>
            <div>&#160;</div>
          </td>
          <td style="width: 20.62%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Urinary tract infection, vaginal infection, upper abdominal pain and diarrhea</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 11.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AG10</font></div>
          </td>
          <td style="width: 10.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Eidos</font></div>
          </td>
          <td style="width: 15.35%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Small molecule that binds and stabilizes TTR in the blood</font></div>
          </td>
          <td style="width: 14.99%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td style="width: 11.35%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Oral</font></div>
          </td>
          <td style="width: 16.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Demonstrated a statistically significant increase in serum TTR concentrations</font></div>
          </td>
          <td style="width: 20.62%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Drug well tolerated with no safety signals</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 11.14%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">CRX-1008</font></div>
          </td>
          <td style="width: 10.44%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Corino Therapeutics</font></div>
          </td>
          <td style="width: 15.35%; vertical-align: middle; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Small molecule repurposed generic drug</font></div>
          </td>
          <td style="width: 14.99%; vertical-align: middle; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td style="width: 11.35%; vertical-align: middle; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Daily oral dose</font></div>
          </td>
          <td style="width: 16.11%; vertical-align: middle; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shows binding and stabilization of TTR in humans</font></div>
          </td>
          <td style="width: 20.62%; vertical-align: middle; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">No drug related adverse events reported</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 11.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Vutrisiran</font></div>
          </td>
          <td style="width: 10.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Alnylam</font></div>
          </td>
          <td style="width: 15.35%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">An RNAi drug conjugated with GalNAC to inhibit TTR mRNA in liver cells</font></div>
          </td>
          <td style="width: 14.99%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3</font></div>
          </td>
          <td style="width: 11.35%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Monthly or quarterly</font></div>
          </td>
          <td style="width: 16.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In healthy volunteers, a single dose showed mean max TTR knockdown of 97%</font></div>
          </td>
          <td style="width: 20.62%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Injection site reactions were reported</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zb10cd3a36af241a1b3d47187835793b0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Taken from public documents including respective company press releases, company presentations, and scientific presentations. Diflunisal efficacy and safety
                    came from the published papers of two investigator sponsored studies, Berk JL, Suhr OB, Obici L, et al. Repurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial. JAMA. 2013;310(24):2658-2667 and Sekijima
                    YS, Toja K, Morita H, et al. Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis. Amyloid. 2015;22(2):79-83.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI is a once weekly, self-administered subcutaneous medicine. TEGSEDI was approved in 2018 in the U.S., EU and Canada
        for the treatment of polyneuropathy caused by hATTR in adult patients. Results from our Phase 3 NEURO-TTR study demonstrated that patients treated with TEGSEDI experienced significant benefit compared to patients treated with placebo across both
        co-primary endpoints: the Norfolk QoL-DN and mNIS+7 a measure of neuropathic disease progression. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The product label for TEGSEDI in the U.S. has a boxed warning for
          thrombocytopenia and glomerulonephritis and requires periodic blood and urine monitoring. TEGSEDI has a Risk Evaluation and Mitigation Strategy, or REMS, program. </font>Our main competition in the U.S. market for TEGSEDI is ONPATTRO
        (patisiran), marketed by Alnylam Pharmaceuticals, Inc. Although ONPATTRO requires intravenous administration by a healthcare provider in a clinical setting every three weeks and pre-treatment with steroids, it does not have a boxed warning or REMS.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 39.6pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Medicine Under Regulatory Review</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">36</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">WAYLIVRA</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe that the following medicines could compete with WAYLIVRA:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z572bfa4155b348f89090f1d2934767e0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 11.97%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine</font></div>
          </td>
          <td style="width: 11.49%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Company</font></div>
          </td>
          <td style="width: 11.37%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Description</font></div>
          </td>
          <td style="width: 9.11%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Phase</font></div>
          </td>
          <td style="width: 12.91%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Admin/Dosing</font></div>
          </td>
          <td style="width: 21.12%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Efficacy(1)</font></div>
          </td>
          <td style="width: 22.02%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Safety(1)</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 11.97%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Metreleptin</font></div>
          </td>
          <td style="width: 11.49%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Novelion Therapeutics</font></div>
            <div>&#160;</div>
          </td>
          <td style="width: 11.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A synthetic form of the hormone leptin</font></div>
          </td>
          <td style="width: 9.11%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3</font></div>
          </td>
          <td style="width: 12.91%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Reconstituted subcutaneous injection</font></div>
          </td>
          <td style="width: 21.12%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">44.4% mean reduction in triglycerides at four months in patients with abnormal triglyceride levels</font></div>
            <div>&#160;</div>
          </td>
          <td style="width: 22.02%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Anti-metreleptin antibodies, hypoglycemia, hypersensitivity, risk of T-cell lymphoma</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 11.97%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Gemcabene</font></div>
          </td>
          <td style="width: 11.49%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Gemphire Therapeutics</font></div>
          </td>
          <td style="width: 11.37%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Monocalcium salt of a dialkyl ether dicarboxylic acid</font></div>
          </td>
          <td style="width: 9.11%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td style="width: 12.91%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Oral, once-daily</font></div>
          </td>
          <td style="width: 21.12%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In a post hoc analysis (n=9) of patients with triglycerides &gt;500 mg/dL, reductions of 59% and 60% from 150 mg and 300</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">mg doses, respectively, were observed</font></div>
          </td>
          <td style="width: 22.02%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In a recent study, in the gemcabene-treatment group, the</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">most frequently occurring adverse events were headache and infection</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z93ca7a94e35c496789189b2c78d16ff5" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Taken from public documents including respective company press releases, company presentations, and scientific presentations.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Metreleptin is being tested in people with FPL who also have NASH. Metreleptin is currently approved for use in the U.S.
        and EU in generalized lipodystrophy, or GL patients. Metreleptin does not affect apoC-III levels. ApoC-III levels have been shown to be elevated in people with FPL, and directly correlate to triglyceride levels.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Gemcabene is being studied in people with severe hypertriglyceridemia, defined as triglycerides above 500 mg/dL. Gemphire
        announced top-line results in June 2018 that Gemcabene met its Phase 2b primary endpoint and demonstrated statistically significant lowering of triglycerides in s<font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;">evere hypertriglyceridemia. The initiation of a Phase 3 study will not take place until the partial clinical hold, which was issued by the FDA in 2004, is lifted.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">To date, WAYLIVRA has shown the highest percent of triglyceride reductions compared to existing treatments, such as
        fibrates, regardless of starting triglyceride levels prior to dosing with WAYLIVRA. Based on our broad Phase 2 data for the treatment of different patients including people with FCS, we believe that WAYLIVRA will work equally well as a single agent
        or in combination with other triglyceride-lowering medicines on the market. If regulatory authorities require us to implement platelet monitoring procedures in the commercial setting, which have yet to be determined, it could impact the future
        competitive profile of WAYLIVRA.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Medicine Currently in Pivotal Trials</font></div>
    <div><br>
    </div>
    <div style="text-align: left; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub></font></div>
    <div style="text-align: justify; text-indent: 39.6pt;"><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe that the following medicines could compete with IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z239a5baa71654c6fad2ddc219877eed0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 14.26%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine</font></div>
          </td>
          <td style="width: 11.09%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Company</font></div>
          </td>
          <td style="width: 10.86%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Medicine Description</font></div>
          </td>
          <td style="width: 9.36%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Phase</font></div>
          </td>
          <td style="width: 12.79%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Admin/Dosing</font></div>
          </td>
          <td style="width: 20.19%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Efficacy(1)</font></div>
          </td>
          <td style="width: 21.44%; vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Safety(1)</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 14.26%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Laquinimod</font></div>
          </td>
          <td style="width: 11.09%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Active Biotech</font></div>
          </td>
          <td style="width: 10.86%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A small molecule that activates selective aryl hydrocarbon receptor</font></div>
          </td>
          <td style="width: 9.36%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td style="width: 12.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Daily oral dose</font></div>
          </td>
          <td style="width: 20.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Did not meet its primary endpoint of slowing disease development, but secondary endpoint of reduction of brain atrophy was met</font></div>
          </td>
          <td style="width: 21.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">No drug related adverse events reported</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 14.26%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">OMS824</font></div>
          </td>
          <td style="width: 11.09%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Omeros</font></div>
          </td>
          <td style="width: 10.86%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A small molecule that targets PDE 10</font></div>
          </td>
          <td style="width: 9.36%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td style="width: 12.79%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Daily oral dose</font></div>
          </td>
          <td style="width: 20.19%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">None reported</font></div>
          </td>
          <td style="width: 21.44%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">None reported</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 14.26%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selistat</font></div>
          </td>
          <td style="width: 11.09%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AOP Orphan</font></div>
          </td>
          <td style="width: 10.86%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">An orally active, selective SIRT1 inhibitor</font></div>
          </td>
          <td style="width: 9.36%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td style="width: 12.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Daily oral dose</font></div>
          </td>
          <td style="width: 20.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">None reported</font></div>
          </td>
          <td style="width: 21.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Safe and tolerable in Phase 1 and Phase 2 study</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 14.26%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">VX15</font></div>
          </td>
          <td style="width: 11.09%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Vaccinex</font></div>
          </td>
          <td style="width: 10.86%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A monoclonal antibody that blocks the activity of SEMA4D</font></div>
          </td>
          <td style="width: 9.36%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td style="width: 12.79%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Monthly intravenous infusions</font></div>
          </td>
          <td style="width: 20.19%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Favored in all brain regions examined, with median increase in FDG uptake from baseline of 8.6% vs placebo control achieving
                significance in the majority of frontal and parietal brain regions analyzed</font></div>
          </td>
          <td style="width: 21.44%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">To date, evaluated patients showed no safety signals</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 14.26%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">WVE-120101/ WVE-120102</font></div>
          </td>
          <td style="width: 11.09%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Wave Life Sciences</font></div>
          </td>
          <td style="width: 10.86%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;Antisense drugs targeting mHTT SNP-1 and SNP-2</font></div>
          </td>
          <td style="width: 9.36%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1b/2a</font></div>
          </td>
          <td style="width: 12.79%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Intrathecal administration</font></div>
          </td>
          <td style="width: 20.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">None reported</font></div>
          </td>
          <td style="width: 21.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">None reported</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z85a661abb7f24b41a745fefb9ee7dbe7" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Taken from public documents including respective company press releases, company presentations, and scientific presentations.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">37</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe that Wave Life Sciences&#8217; WVE-120101 and WVE-120102, being developed for Huntington&#8217;s Disease, could compete
        directly against <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS-HTT</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. These medicines are antisense medicines administered intrathecally, targeting mHTT SNP-1 and SNP-2, respectively. Wave
        Life Sciences is currently conducting two simultaneous Phase 1b/2a clinical trials, enrolling adults with early manifest Huntington&#8217;s disease who carry a single nucleotide polymorphism, or SNP, at the SNP1 (study name: PRECISION HD1) and SNP2
        (study name: PRECISION HD2) location, with their data readouts expected in the first half of 2019.</font></div>
    <div><br>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:823d8add-7585-49e6-8c98-c0ea91e05bcc">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Employees</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As of February 20, 2019, we employed 737 people, including 248 Akcea employees. A significant number of our management and
        professional employees have had prior experience with pharmaceutical, biotechnology or medical product companies. Collective bargaining agreements do not cover any of our employees, and management considers relations with our employees to be good.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Executive Officers of Ionis</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following sets forth certain information regarding our executive officers as of February 20, 2019:</font></div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="ze0c2a86ba113416bb1cb7d46cddf99d8" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 29.39%; vertical-align: bottom; background-color: #FFFFFF; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Name</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 6.67%; vertical-align: bottom; background-color: #FFFFFF; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Age</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 59.14%; vertical-align: bottom; background-color: #FFFFFF; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Position</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.39%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Stanley T. Crooke, M.D., Ph.D.</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 6.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">73</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 59.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Chairman, Chief Executive Officer and President</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.39%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Brett P. Monia, Ph.D.</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 6.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">57</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 59.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Chief Operating Officer</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.39%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">C. Frank Bennett, Ph.D.</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 6.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">62</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 59.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Senior Vice President, Antisense Research</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.39%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Damien McDevitt, Ph.D.</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 6.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">52</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 59.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Chief Business Officer</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.39%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Richard S. Geary, Ph.D.</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 6.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">61</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 59.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Senior Vice President, Development</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.39%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elizabeth L. Hougen</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 6.67%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">57</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td style="width: 59.14%; vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Senior Vice President, Finance and Chief Financial Officer</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.39%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Patrick R. O&#8217;Neil, Esq.</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 6.67%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">45</font></div>
          </td>
          <td style="width: 2.4%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 59.14%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Senior Vice President, Legal, General Counsel, Chief Compliance Officer and Corporate Secretary</font></div>
          </td>
        </tr>

    </table>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Management Transitions</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2020, Dr. Crooke, our founder and Chief Executive Officer, plans to transition from Chief Executive Officer to
        Executive Chairman of our Board of Directors. As Executive Chairman, Dr. Crooke will continue to be responsible for the activities of the board and will remain active in the company, providing strategic advice and continuing to participate in the
        scientific activities. Our board has selected Dr. Monia, who has been our Chief Operating Officer for the last year and a member of our team since our founding nearly 30 years ago, to serve as our Chief Executive Officer starting in January 2020.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">STANLEY T. CROOKE, M.D., Ph.D.</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Chairman, Chief Executive Officer and President</font></div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dr. Crooke is a founder of Ionis and has been Chief Executive Officer and a Director since January 1989. He was elected
        Chairman of the Board in February 1991. Prior to founding Ionis, from 1980 until January 1989, Dr. Crooke was employed by SmithKline Beckman Corporation, a pharmaceutical company, where his titles included President of Research and Development of
        SmithKline and French Laboratories.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">BRETT P. MONIA, Ph.D.</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Chief Operating Officer and Senior Vice President, Translational Medicine</font></div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 38.15pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dr. Monia was promoted to Chief Operating Officer in January 2018 and to Senior Vice President in January 2012. From
        February 2009 to January 2012, Dr. Monia served as our Vice President, Drug Discovery and Corporate Development and from October 2000 to February 2009, he served as our Vice President, Preclinical Drug Discovery. From October 1989 to October 2000
        he held various positions within our Molecular Pharmacology department.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">C. FRANK BENNETT, Ph.D.</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Senior Vice President, Antisense Research</font></div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dr. Bennett was promoted to Senior Vice President, Antisense Research in January 2006. From June 1995 to January 2006, Dr.
        Bennett served as our Vice President, Research. From March 1993 to June 1995, he was Director, Molecular Pharmacology, and from May 1992 to March 1993, he was an Associate Director in our Molecular and Cellular Biology department. Prior to joining
        Ionis in 1989, Dr. Bennett was employed by SmithKline and French Laboratories in various research positions. He is an external member of the Scientific Advisory Board of Experimental Therapeutics Center in Singapore and the Hereditary Disease
        Foundation.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">DAMIEN McDEVITT, Ph.D.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Chief Business Officer</font></div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="background-color: #FBFBFB;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dr. McDevitt joined Ionis in June 2018 as our Chief Business Officer. In October 2018, he was appointed to the board of
          directors of our majority-owned affiliate, Akcea Therapeutics, Inc. Previously, Dr. McDevitt was Senior Vice President, Corporate Development at ACADIA Pharmaceuticals. Prior to ACADIA, he was at GSK for more than two decades. He served in
          various roles with increasing responsibility including vice president, head of business development for R&amp;D Extended Therapy areas, head of Worldwide Business Development Asia and head of GSK&#8217;s R&amp;D West Coast Innovation Center.</font></div>
      <div><br>
      </div>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">38</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">RICHARD S. GEARY, Ph.D.</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Senior Vice President, Development</font></div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dr. Geary was promoted to Senior Vice President, Development in August 2008. From August 2003 to August 2008, Dr. Geary
        served as our Vice President, Preclinical Development. From November 1995 to August 2003, he held various positions within the Preclinical Development department. Prior to joining Ionis in 1995, Dr. Geary was Senior Research Scientist and Group
        Leader for the bioanalytical and preclinical pharmacokinetics group in the Applied Chemistry Department at Southwest Research Institute.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">ELIZABETH L. HOUGEN</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Senior Vice President, Finance and Chief Financial Officer</font></div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ms. Hougen was promoted to Senior Vice President, Finance and Chief Financial Officer in January 2013. From January 2007
        to December 2012, Ms. Hougen served as our Vice President, Finance and Chief Accounting Officer and from May 2000 to January 2007, she served as our Vice President, Finance. Prior to joining Ionis in 2000, Ms. Hougen was Executive Director, Finance
        and Chief Financial Officer for Molecular Biosystems, Inc., a public biotechnology company.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">PATRICK R. O&#8217;NEIL, Esq.</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Senior Vice President, Legal, General Counsel, Chief Compliance Officer and
        Corporate Secretary</font></div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Mr. O&#8217;Neil was promoted to Senior Vice President, Legal and General Counsel in January 2013. Mr. O&#8217;Neil also serves as our
        Chief Compliance Officer and Corporate Secretary. From September 2010 to January 2013, Mr. O&#8217;Neil served as our Vice President, Legal and General Counsel and from January 2009 to September 2010, he served as our Vice President, Legal and Senior
        Transactions Counsel. From October 2001 to January 2009 he held various positions within our Legal department. Prior to joining Ionis, Mr. O&#8217;Neil was an associate at Cooley LLP.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:14c93476-329a-46c1-b2d1-508c3071b21d">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 1A. RISK FACTORS</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Investing in our securities involves a high degree of risk. You should consider carefully 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Risks Associated with our Ionis Core and Akcea Therapeutics Businesses</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If the market does not accept our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, we are not likely to generate
        revenues or become consistently profitable.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Even if our medicines are authorized for marketing, including SPINRAZA, TEGSEDI and WAYLIVRA, our success will depend upon
        the medical community, patients and third-party payors accepting our medicines as medically useful, cost-effective and safe. 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. We and our partners may not successfully commercialize additional medicines.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additionally, in many of the markets where we may sell our medicines in the future, if we cannot agree with the government
        regarding the price we can charge for our medicines, then we may not be able to sell our medicines in that market. Similarly, cost control initiatives by governments or third-party payors could decrease the price received for our medicines or
        increase patient coinsurance to a level that makes our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, unaffordable.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The degree of market acceptance for our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, depends upon a number of
        factors, including the:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z64f0c415297e4c7f96e1c36432937fe8" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">receipt and scope of marketing authorizations;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z4878fb7e980e49d0b8327752d6d80c23" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">establishment and demonstration in the medical and patient community of the efficacy and safety of our medicines and their potential advantages over competing
                    products;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zd67d49e7710e40cbbfda5b25d66b2cd0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">cost and effectiveness of our medicines compared to other available therapies;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z698e283423604a43b284abc835fca41d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">patient convenience of the dosing regimen for our medicines; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zc1f5bfc977c3413db1c5bd5aaaafa43c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">reimbursement policies of government and third-party payors.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Based on the profile of our medicines, physicians, patients, patient advocates, payors or the medical community in general
        may not accept and/or use any medicines that we may develop.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">39</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, the product label for TEGSEDI in
          the U.S. has a boxed warning for thrombocytopenia and glomerulonephritis, requires periodic blood and urine monitoring, and TEGSEDI has a Risk Evaluation and Mitigation Strategy, or REMS, program. </font>Our main competition in the U.S. market
        for TEGSEDI is ONPATTRO (patisiran), marketed by Alnylam Pharmaceuticals, Inc. Although ONPATTRO requires intravenous administration and pre-treatment with steroids, it does not have a boxed warning or REMS. <font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">Additionally, in the clinical studies with WAYLIVRA, declines in platelet counts were observed in many patients and some patients discontinued the studies because of platelet declines. Therefore, we
          expect the product label for WAYLIVRA will require periodic blood monitoring. In each case, these label requirements could negatively affect our ability to attract and retain patients for these medicines. We believe that the enhanced monitoring
          we have implemented to support early detection and management of these issues can help manage these safety issues so that patients can continue treatment. Since implementation of the enhanced monitoring, serious platelet events have been
          infrequent. While we believe we and Akcea can better maintain patients on TEGSEDI and WAYLIVRA through patient-centric commercial approaches where we plan to have greater involvement with physicians and patients, if we cannot effectively maintain
          patients on TEGSEDI or WAYLIVRA, we may not be able to generate substantial revenue from TEGSEDI or WAYLIVRA sales.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If we or our partners fail to compete effectively, our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, will not
        contribute significant revenues.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our competitors engage in drug discovery throughout the world, are numerous, and include, among others, major
        pharmaceutical companies and specialized biopharmaceutical firms. Other companies engage in developing antisense technology. Our competitors may succeed in developing medicines that are:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zd9feefe2c4fd4fa09a3a66733acee992" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">priced lower than our medicines;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zfc2b51db4fc0488295516af8d4846d6e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">reimbursed more favorably by government and other third-party payors than our medicines;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z09170bc793fa4dfea9fb404ae4c2b16a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">safer than our medicines;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z8a3fdf41de724c42953e28ba434e018a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">more effective than our medicines; or</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z279a35a2e7e54426a0ed92e7e7993004" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">more convenient to use than our medicines.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">These competitive developments could make our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, obsolete or
        non-competitive.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Certain of our partners are pursuing other technologies or developing other medicines either on their own or in
        collaboration with others, including our competitors, to treat the same diseases our own collaborative programs target. Competition may negatively impact a partner&#8217;s focus on and commitment to our medicines and, as a result, could delay or
        otherwise negatively affect the commercialization of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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. Marketing and sales capability is another factor relevant to the competitive position of our medicines,
        and we will primarily rely on our partners and Akcea to provide this capability.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">There are several pharmaceutical and biotechnology companies engaged in the development or commercialization of products
        against targets that are also targets of products in our development pipeline. For example, Zolgensma (AVXS-101), Risdiplam (RG7916), Reldesemtiv and Firdapse could compete with SPINRAZA, and ONPATTRO (approved in the U.S. and Europe for a similar
        indication as TEGSEDI), Tafamadis, AG10, CRX-1008 and Vutrisiran could compete with TEGSEDI. Also, Metreleptin and Gemcabene could compete with WAYLIVRA, while Laquinimod, OMS823, Selistat, VX15, WVE-120101 and WVE-120102 could compete with
        IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Following approval, our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA could be subject to regulatory limitations.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Following approval of a medicine, we and our partners must comply with comprehensive government regulations regarding the
        manufacture, marketing and distribution of drug products. We or our partners may not obtain the labeling claims necessary or desirable to successfully commercialize our drug products, including SPINRAZA, TEGSEDI and WAYLIVRA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The FDA and foreign regulatory authorities have the authority to impose significant restrictions on an approved drug
        product through the product label and on advertising, promotional and distribution activities. For example:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zdcfbb1fc241a430881b00f87fd064f8a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">U.S.</font>, TEGSEDI&#8217;s label contains a boxed warning for
                    thrombocytopenia and glomerulonephritis;</font></div>
              </td>
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        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zf9672baa91ab4f36839fea7caea75e57" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI requires periodic blood and urine monitoring; and</font></div>
              </td>
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        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z61b10b9b3a6e4987a5d124c4eef0f505" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">in the U.S. TEGSEDI is available only through a Risk Evaluation and Mitigation Strategy, or REMS, program.</font></div>
              </td>
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        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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. If the results of such post-marketing studies are not satisfactory, the FDA or a foreign regulatory authority may withdraw marketing authorization or
        may condition continued marketing on commitments from us or our partners that may be expensive and/or time consuming to fulfill.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 39.6pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If we or others identify side effects after any of our drug products are on the market, or if manufacturing problems
        occur subsequent to regulatory approval, we or our partners may lose regulatory approval, or we or our partners may need to conduct additional clinical studies and/or change the labeling of our drug products, including <font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA, TEGSEDI and WAYLIVRA.</font></font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">40</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">We depend on our collaboration with Biogen for the development and commercialization of SPINRAZA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have entered into a collaborative arrangement with Biogen to develop and commercialize SPINRAZA. We entered into this
        collaboration primarily to:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zd3564a12792d4a86a91201e63784f0ea" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">fund our development activities for SPINRAZA;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z0dddf2bf12e74b3c8d0973645ba9bafc" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">seek and obtain regulatory approvals for SPINRAZA; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z1162f97fe9524f03b80c973987e9245c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">successfully commercialize SPINRAZA.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are relying on Biogen to obtain additional regulatory approvals for SPINRAZA, and successfully commercialize SPINRAZA.
        In general, we cannot control the amount and timing of resources that Biogen devotes to our collaboration. If Biogen fails to further develop SPINRAZA, obtain additional regulatory approvals for SPINRAZA, or commercialize SPINRAZA, or if Biogen&#8217;s
        efforts are not effective, our business may be negatively affected.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our collaboration with Biogen may not continue for various reasons. Biogen can terminate our collaboration at any time. If
        Biogen stops developing or commercializing SPINRAZA, we would have to seek or spend additional funding, and SPINRAZA&#8217;s commercialization may be harmed or delayed.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our collaboration with Biogen may not result in the continued successful commercialization of SPINRAZA. If Biogen does not
        continue to successfully commercialize SPINRAZA, we will receive limited revenues for SPINRAZA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If Akcea cannot optimize and maintain effective marketing and sales capabilities or enter into agreements with
        third&#160;parties to market and sell TEGSEDI, we may not generate significant product&#160;revenue from TEGSEDI.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">To successfully commercialize TEGSEDI Akcea must successfully manage its marketing, sales and distribution capabilities or
        make arrangements with third parties to perform these services. Akcea may not be successful in doing so. To commercialize TEGSEDI in the initial indications Akcea is pursuing, Akcea will need to optimize and maintain a specialty sales force in each
        global region it expects to market TEGSEDI, supported by case managers, reimbursement specialists, partnerships with specialty pharmacies, injection training, routine blood and urine monitoring and a medical affairs team. Akcea may seek to further
        penetrate markets by expanding its sales force or through strategic partnerships with other pharmaceutical or biotechnology companies or third-party sales organizations.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Even though certain members of Akcea&#8217;s management team and other employees have experience commercializing drug products,
        Akcea has no prior experience marketing, selling or distributing drug products, and there are significant risks involved in building and managing a commercial infrastructure. It will be expensive and time consuming for Akcea to maintain its own
        sales force and related compliance protocols to market TEGSEDI. Akcea may never successfully optimize or manage this capability and any failure could preclude the successful commercialization of TEGSEDI. Akcea and its partners, if any, will have to
        compete with other companies to recruit, hire, train, manage and retain marketing and sales personnel.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea incurred expenses prior to the launch of TEGSEDI to integrate and manage the associated marketing and sales
        infrastructure. If regulatory requirements or other factors cause the commercial launch of TEGSEDI to be less successful than expected, Akcea will have incurred expenses for having invested in these capabilities prior to realizing any significant
        revenue from sales of TEGSEDI. Akcea&#8217;s sales force and marketing teams may not successfully commercialize TEGSEDI.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">To the extent we and Akcea decide to rely on third parties to commercialize TEGSEDI in a particular geographic market,
        such as the collaboration Akcea has with PTC Therapeutics to commercialize TEGSEDI in Latin America, we may receive less revenue than if Akcea commercialized TEGSEDI by itself. Further we would have less control over the sales efforts of any other
        third parties involved in commercializing TEGSEDI.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If Akcea cannot effectively build and manage its distribution, medical affairs, market access, marketing and sales
        infrastructure, or find a suitable third party to perform such functions, the commercial launch and sales of TEGSEDI may be delayed, less successful or precluded. Such events may result in decreased sales and lower revenue, which could have a
        material adverse effect on our business, prospects, financial condition and results of operations.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If government or other third-party payors fail to provide adequate coverage and payment rates for our medicines, including
        SPINRAZA, TEGSEDI and WAYLIVRA, our revenue will be limited.</font></div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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 payors. The majority of people 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 drug products 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Third-party payors, 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 drug products exists among third-party payors. Therefore, coverage and reimbursement for drug products can differ significantly
        from payor to payor. Further, we believe that future coverage and reimbursement will likely be subject to increased restrictions both in the U.S. and in international markets. For example, in the U.S., recent health reform measures have resulted in
        reductions in Medicare and other healthcare funding, and there have been several U.S. Congressional inquiries and proposed federal legislation designed to, among other things, reform government program reimbursement methodologies for drug products
        and bring more transparency to drug pricing. Third-party coverage and reimbursement for our products or 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.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">41</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If Biogen cannot manufacture finished drug product for SPINRAZA or the post-launch supply of the active drug substance for
        SPINRAZA, SPINRAZA may not maintain commercial success.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Biogen is responsible for the long-term supply of both SPINRAZA drug substance and finished drug product. Biogen may not
        be able to reliably manufacture SPINRAZA drug substance and drug product to support the long-term commercialization of SPINRAZA. If Biogen cannot reliably manufacture SPINRAZA drug substance and drug product, SPINRAZA may not maintain commercial
        success, which will harm our ability to generate revenue.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If we or our partners fail to obtain regulatory approval for our medicines, including WAYLIVRA, and additional approvals
        for SPINRAZA and TEGSEDI, we or our partners cannot sell them in the applicable markets.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We cannot guarantee that any of our medicines, including WAYLIVRA, will be considered safe and effective, or will be
        approved for commercialization. In addition, we cannot guarantee that SPINRAZA and TEGSEDI will be approved in additional markets or for additional indications. We and our partners must conduct time-consuming, extensive and costly clinical studies
        to show the safety and efficacy of each of our medicines before they can be approved for sale. We must conduct these studies in compliance with FDA regulations and with comparable regulations in other countries.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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, including WAYLIVRA, for marketing or additional marketing authorizations for SPINRAZA or TEGSEDI. 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, the agency will not approve the specific medicine or
          will require additional studies, which can be time consuming and expensive and which will delay or harm commercialization of the medicine. For example, Akcea received a CRL from the FDA and a preliminary notice of noncompliance withdrawal letter
          from Health Canada for WAYLIVRA. As result, Akcea may need to submit additional data to the FDA and Health Canada or conduct additional clinical studies before obtaining marketing authorization, which would be expensive and cause delays. </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The CHMP of the EMA has adopted a positive opinion recommending conditional marketing authorization of WAYLIVRA as an adjunct to diet in adult patients with genetically
          confirmed FCS who are at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate. The positive opinion will now be referred to the EC, which grants marketing authorization for medicines in the
          European Union, as well as to European Economic Area members Iceland, Liechtenstein and Norway, however, the EC </font>may decide not to adopt the CHMP&#8217;s positive opinion<font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif;">.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Failure to receive marketing authorization for WAYLIVRA or our other medicines, or failure to receive additional marketing
        authorizations for SPINRAZA or TEGSEDI, 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Drug discovery and development has inherent risks and the historical failure rate for drugs is high. Antisense drugs are a
        relatively new approach to therapeutics. If we cannot demonstrate that our medicines are safe and effective for human use, we may need to abandon one or more of our drug development programs.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the past, we have invested in clinical studies of medicines that have not met the primary clinical end points in their
        Phase 3 studies. Similar results could occur in clinical studies for our medicines, including the study of WAYLIVRA in patients with FPL and the study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in patients with Huntington&#8217;s disease. If any of our medicines in
        clinical studies, including WAYLIVRA and IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, do not show sufficient efficacy in patients with the targeted indication, it could negatively impact our development and commercialization goals for these medicines and our stock
        price could decline.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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, including the Phase 3 study of WAYLIVRA in patients with FPL and the pivotal study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in patients with Huntington&#8217;s disease. There are a
        number of factors that could cause a clinical study to fail or be delayed, including:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z4927e3217b5d411993ef0e399ce5cac0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">the clinical study may produce negative or inconclusive results;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z2072185e33fd45ee8cfda42b6cc9f191" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">regulators may require that we hold, suspend or terminate clinical research for noncompliance with regulatory requirements;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z5afa4b7c35114d5bab3afaa772523c13" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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
                    in the trial;</font></div>
              </td>
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        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="za965b58959304978ae1b9c37b864c672" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">we may decide, or regulators may require us, to conduct additional preclinical testing or clinical studies;</font></div>
              </td>
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        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z0a9b9ee442f646fca3d3b85fd8e01555" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">enrollment in our clinical studies may be slower than we anticipate;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="za2a22afd1a134a8f95c6df1731cc5625" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z781cf3807530450ebb95fddfe7f4689a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">the cost of our clinical studies may be greater than we anticipate; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zf528df538249498892bc6701f8c0b19b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">the supply or quality of our medicines or other materials necessary to conduct our clinical studies may be insufficient, inadequate or delayed.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">42</font></div>
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In addition, our current medicines, including
          SPINRAZA, TEGSEDI and WAYLIVRA, are chemically similar to each other. As a result, a safety observation we encounter with one of our medicines could have, or be perceived by a regulatory authority to have, an impact on a different drug we are
          developing.&#160;This could cause the FDA and other regulators to ask questions or take actions that could harm or delay our ability to develop and commercialize our medicines or increase our costs. For example, the FDA or other regulatory agencies
          could request, among other things, any of the following regarding one of our medicines: additional information or commitments before we can start or continue a clinical study, protocol amendments, increased safety monitoring, additional product
          labeling information, and post-approval commitments. Similarly, we have an ongoing Phase 3 study of WAYLIVRA in patients with FPL, an ongoing open-label extension study of WAYLIVRA in patients with FCS, an ongoing open-label extension study of
          TEGSEDI </font>and expanded access programs for each medicine.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> Adverse events or results from these studies could negatively impact our current or planned marketing
          approval applications for WAYLIVRA in patients with FCS or the commercial opportunity for each product.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Any failure or delay in the clinical studies, including the Phase 3 study for WAYLIVRA in patients with FPL and the
        pivotal study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in patients with Huntington&#8217;s disease, could reduce the commercial potential or viability of our medicines.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If we cannot manufacture our medicines or contract with a third party to manufacture our medicines at costs that allow us
        to charge competitive prices to buyers, we cannot market our products profitably.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">To successfully commercialize any of our medicines, we or our partner would need to establish large-scale commercial
        manufacturing capabilities either on our own or through a third-party manufacturer. We and Akcea will rely on third-party manufacturers to supply the drug substance and drug product for TEGSEDI and WAYLIVRA. In addition, as our drug development
        pipeline increases and matures, we will have a greater need for clinical trial and commercial manufacturing capacity. 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 may not be able to manufacture our
        medicines at a cost or in quantities necessary to make commercially successful products.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Also, manufacturers, including us, must adhere to the FDA&#8217;s current Good Manufacturing Practices regulations and similar
        regulations in foreign countries, which the applicable regulatory authorities enforce through facilities inspection programs. We and our contract manufacturers may not comply or maintain compliance with Good Manufacturing Practices, or similar
        foreign regulations. Non-compliance could significantly delay or prevent receipt of marketing authorization for our medicines, including authorizations for SPINRAZA, TEGSEDI and WAYLIVRA, or result in enforcement action after authorization that
        could limit the commercial success of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">We depend on third parties to conduct our clinical studies for our medicines and any failure of those parties to fulfill
        their obligations could adversely affect our development and commercialization plans.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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, INC Research Toronto, Inc. and Medpace for the clinical
        studies for our medicines, including TEGSEDI and WAYLIVRA. We rely heavily on these parties for successful execution of our clinical studies, but do not control many aspects of their activities. For example, the investigators are not our employees.
        However, we are responsible for ensuring that these third parties conduct each of our clinical studies in accordance with the general investigational plan and approved protocols for the study. Third parties may not complete activities on schedule
        or may not conduct our clinical studies in accordance with regulatory requirements or our stated protocols. The failure of these third parties to carry out their obligations or a termination of our relationship with these third parties could delay
        or prevent the development, marketing authorization and commercialization of our medicines, including authorizations for WAYLIVRA or additional authorizations for SPINRAZA and TEGSEDI.</font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Risks Associated with our Businesses as a Whole</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">We have incurred losses, and our business will suffer if we fail to consistently achieve profitability in the future.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Because drug discovery and development requires substantial lead-time and money prior to commercialization, our expenses
        have historically exceeded our revenue since we were founded in January 1989. As of December 31, 2018, we had an accumulated deficit of approximately $1.0 billion and stockholders&#8217; equity of approximately $1,187.2 million. Most of our historical
        losses resulted from costs incurred in connection with our research and development programs and from selling, general and administrative costs associated with our operations. Most of our income has come from collaborative arrangements, including
        commercial revenue from royalties and R&amp;D revenue, with additional income from research grants and the sale or licensing of our patents, as well as interest income. If we do not continue to earn substantial revenue, we may incur additional
        operating losses in the future. We may not successfully develop any additional products or achieve or sustain future profitability.</font></div>
    <div><br>
    </div>
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      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">43</font></div>
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    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Our ability to use our net operating loss carryovers and certain other tax attributes may be limited.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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 that provision, we can carryforward our NOLs to offset our future taxable income, if any, until such NOLs are used or expire. The same is true of other unused tax attributes,
        such as tax credits.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the Tax Cut and Jobs Act of 2017, or the Tax Act, federal net operating losses incurred in 2018 and in future years
        may be carried forward indefinitely, but the deductibility of such federal net operating losses is limited.&#160;It is uncertain if and to what extent various states will conform to the newly enacted federal tax law.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In addition, under Section 382 of the Internal Revenue Code of 1986, as amended, and corresponding provisions of state
        law, if a corporation undergoes an &#8220;ownership change,&#8221; which is generally defined as a greater than 50 percent change, by value, in its equity ownership over a three-year period, the corporation&#8217;s ability to use its pre-change net operating loss
        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 net operating loss carryforwards or other tax attributes is materially limited, it would harm our future operating results by effectively increasing our future tax obligations.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Since corporate partnering is a significant part of our strategy to fund the development 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our corporate partners are developing and/or funding many of the medicines in our development pipeline. If any of these
        pharmaceutical companies stops developing and/or funding these medicines, our business could suffer and we may not have, or be willing to dedicate, the resources available to develop these medicines on our own.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our collaborators can terminate their relationships with us under certain circumstances, many of which are outside of our
        control. For example, as part of a reprioritization of its pipeline and strategic review of its rare disease business, GSK declined its option on TEGSEDI and IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In addition to receiving funding, we enter into collaborative arrangements with third parties to:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z9fc653d954734875a6887f8a7b76f5da" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">conduct clinical studies;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zd3832e5220af411dad8c81dabf25cd79" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">seek and obtain marketing authorization; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zdb1cbe178ee8463a960ae2f75a77fe7b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">manufacture, market and sell our medicines.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Once we have secured a collaborative arrangement to further develop and commercialize one of our drug development
        programs, such as our collaborations with AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis and Roche, these collaborations may not continue or result in commercialized medicines, or may not progress as quickly as we first anticipated.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, a collaborator such as AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis or Roche, could determine that it
        is in its financial interest to:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z5f257f56df4447e8b1d87bce573b4182" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">pursue alternative technologies or develop alternative products that may be competitive with the drug that is part of the collaboration with us;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z425a7fed524c43fcb464c984553e3bb1" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">pursue higher-priority programs or change the focus of its own development programs; or</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z675b61581e274a94909ec21adc9a6f1f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">choose to devote fewer resources to our medicines than it does for its own medicines.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If any of these occur, it could affect our partner&#8217;s commitment to the collaboration with us and could delay or otherwise
        negatively affect the commercialization of our medicines, including SPINRAZA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If we do not progress in our programs as anticipated, the price of our securities could decrease.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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 drug will enter the clinic, when we anticipate completing a clinical study, or when we anticipate filing an application for, or obtaining, marketing authorization. We base our estimates on present facts and a
        variety of assumptions. Many underlying assumptions are outside of our control. If we do not achieve milestones in accordance with our or our investors&#8217; expectations, including milestones related to SPINRAZA, TEGSEDI and WAYLIVRA, the price of our
        securities could decrease.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">44</font></div>
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    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If we cannot protect our patents or our other proprietary rights, others may compete more effectively against us.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our success depends to a significant degree upon whether we can continue to develop and secure 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. 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Intellectual property litigation could be expensive and prevent us from pursuing our programs.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time we have to defend our intellectual property rights. If we are involved in an intellectual property
        dispute, we sometimes need to litigate to defend our rights or assert them against others. Disputes can involve arbitration, litigation or proceedings declared by the U.S. Patent and Trademark Office or the International Trade Commission or foreign
        patent authorities. Intellectual property litigation can be extremely expensive, and this expense, as well as the consequences should we not prevail, could seriously harm our business.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If we fail to obtain timely funding, we may need to curtail or abandon some of our programs.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Many of our medicines are undergoing clinical studies or are in the early stages of research and development. Most of our
        drug programs will require significant additional research, development, preclinical and/or clinical testing, marketing authorization and/or commitment of significant additional resources prior to their successful commercialization. As of December
        31, 2018, we had cash, cash equivalents and short-term investments equal to $2.1 billion. If we do not meet our goals to successfully commercialize our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, or to license our medicines and proprietary
        technologies, we will need additional funding in the future. Our future capital requirements will depend on many factors, such as the following:</font></div>
    <div><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zbb5ee328471b4981819a69cde987a14e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">successful commercialization for SPINRAZA and TEGSEDI;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zf9e324cceadd4eb0b943418628607975" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">marketing approvals for WAYLIVRA;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="ze59ca204b2b34acbb17c8f4c99422266" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">the profile and launch timing of our medicines, including TEGSEDI and WAYLIVRA;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z5e35f9e2e8b04fdaa8e619494d9743ec" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">changes in existing collaborative relationships and our ability to establish and maintain additional collaborative arrangements;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z679b87cbc5a84d178bdabc4abc1684e8" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">continued scientific progress in our research, drug discovery and development programs;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z781fb856a91e403bb05bd8bdf447bc68" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">the size of our programs and progress with preclinical and clinical studies;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z3023327707d2456bacd3ef4931470126" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">the time and costs involved in obtaining marketing authorizations; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z481e25e850b64141b438ea1013aa5f6c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">competing technological and market developments, including the introduction by others of new therapies that address our markets.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If we need additional funds, we may need to raise them through public or private financing. Additional financing may not
        be available at all or on acceptable terms. If we raise additional funds by issuing equity securities, the shares of existing stockholders will be diluted and the price, as well as the price of our other securities, may decline. If adequate funds
        are not available or not available on acceptable terms, we may have to cut back on one or more of our research, drug discovery or development programs. Alternatively, we may obtain funds through arrangements with collaborative partners or others,
        which could require us to give up rights to certain of our technologies or medicines.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If our planned management transition is not successful our business could suffer.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2020, Dr. Crooke, our founder and Chief Executive Officer, plans to transition from Chief Executive Officer to
        Executive Chairman of our Board of Directors. As Executive Chairman, Dr. Crooke will continue to be responsible for the activities of the board and will remain active in the company, providing strategic advice and continuing to participate in the
        scientific activities. Our board has selected Dr. Monia, who has been our Chief Operating Officer for the last year and a member of our team since our founding nearly 30 years ago, to serve as our Chief Executive Officer starting in January 2020.&#160;
        If this transition is not successful, our business could suffer.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are dependent on the principal members of our management and scientific staff. We do not have employment agreements
        with any of our executive officers that would prevent them from leaving us. The loss of our management and key scientific employees might slow the achievement of important research and development goals. It is also critical to our success that we
        recruit and retain qualified scientific personnel to perform research and development work. We may not be able to attract and retain skilled and experienced scientific personnel on acceptable terms because of intense competition for experienced
        scientists among many pharmaceutical and health care companies, universities and non-profit research institutions. In addition, failure to succeed in clinical studies may make it more challenging to recruit and retain qualified scientific
        personnel.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">45</font></div>
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    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If the price of our securities continues to be highly volatile, this could make it harder for you to liquidate your
        investment and could increase your risk of suffering a loss.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The market price of our common stock, like that of the securities of many other biopharmaceutical companies, has been and
        is likely to continue to be highly volatile. These fluctuations in our common stock price may significantly affect the trading price of our securities. During the 12 months preceding December 31, 2018, the market price of our common stock ranged
        from $59.81 to $39.07 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, governmental regulation, marketing authorization, changes in payors&#8217; reimbursement policies, developments in patent or other proprietary rights, public concern regarding the safety of our medicines
        and general market conditions.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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. 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 drug products, 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zbdd0ee41c950414ea3eca685a74c06c2" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">interruption of our research, development and manufacturing efforts;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z4264dc8481e948bba3777c2a0af6736e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">injury to our employees and others;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zd86b4195e97d4b93819c50d7a5594434" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">environmental damage resulting in costly clean up; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zd789e60f10a24f69adaddf0e7b550a6d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In such an event, we may be held liable for any resulting damages, and any liability could exceed our resources. Although
        we carry insurance in amounts and types that we consider commercially reasonable, we do not have insurance coverage for losses relating to an interruption of our research, development or manufacturing efforts caused by contamination, and the
        coverage or coverage limits of our insurance policies may not be adequate. If our losses exceed our insurance coverage, our financial condition would be affected.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">If a natural or man-made disaster strikes our research, development or manufacturing facilities or otherwise affects our
        business, it could delay our progress developing and commercializing our medicines.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We manufacture our research and clinical supplies in a manufacturing facility located in Carlsbad, California. We
        manufacture the finished drug product for TEGSEDI and WAYLIVRA at third-party contract manufacturers. The facilities and the equipment we 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 our contract manufacturers may be harmed by natural or man-made disasters, including, without limitation, earthquakes, floods, fires and acts of terrorism; and
        if our facilities are affected by a disaster, our development and commercialization efforts would be delayed. Although we possess insurance for damage to our property and the disruption of our business from casualties, 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Provisions in our certificate of incorporation, other agreements and Delaware law may prevent stockholders from receiving
        a premium for their shares.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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&#160;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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">46</font></div>
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Future sales of our common stock in the public market could adversely affect the trading price of our securities.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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 10.3 million shares of our common stock upon conversion of our convertible senior notes. The addition of any of these shares into the public
        market may have an adverse effect on the price of our securities.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Each year we are required to evaluate our internal controls systems in order to allow management to report on and our
        Independent Registered Public Accounting Firm to attest to, our internal controls as required by Section 404 of the Sarbanes-Oxley Act. As a result, we continue to incur additional expenses and divert our management&#8217;s time to comply with these
        regulations. In addition, if we cannot continue to comply with the requirements of Section 404 in a timely manner, we might be subject to sanctions or investigation by regulatory authorities, such as the SEC, the Public Company Accounting Oversight
        Board, or PCAOB, or The Nasdaq Global Select Market. Any such action could adversely affect our financial results and the market price of our common stock.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The SEC and other regulators have continued to adopt new rules and regulations and make additional changes to existing
        regulations that require our compliance. On July 21, 2010, the Dodd-Frank Wall Street Reform and Protection Act, or the Dodd-Frank Act, was enacted. There are significant corporate governance and executive compensation-related provisions in the
        Dodd-Frank Act that require the SEC to adopt, or where the SEC has adopted, additional rules and regulations in these areas such as &#8220;say on pay&#8221; and proxy access. Stockholder activism, the current political environment and the current high level of
        government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which may lead to additional compliance costs and impact the manner in which we operate our business.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Changes in tax laws, regulations and treaties could affect our future taxable income.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A change in tax laws, treaties or regulations, or their interpretation, of any country in which we operate could
        materially affect us.&#160; For example, the Tax Act represented a substantial change to tax laws in the U.S. However, it did not have a material impact on our financial statements because we maintained a valuation allowance on all of our net operating
        losses and other deferred tax assets as of December 31, 2017. Over the next several years we expect to utilize our net operating losses and other deferred tax assets, and any future changes in tax laws could have a material effect on our business.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">We could be subject to additional tax liabilities.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are subject to U.S. federal, state, local and sales taxes in the U.S. and foreign income taxes, 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Negative conditions in the global credit markets and financial services and other industries may adversely affect our
        business.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The global credit markets, the financial services industry, the U.S. capital markets, and the U.S. economy as a whole have
        in the past experienced periods of substantial turmoil and uncertainty characterized by unprecedented intervention by the U.S. federal government and the failure, bankruptcy, or sale of various financial and other institutions. It is possible that
        a crisis in the global credit markets, the U.S. capital markets, the financial services industry or the U.S. economy may adversely affect our business, vendors and prospects, as well as our liquidity and financial condition. More specifically, our
        insurance carriers and insurance policies covering all aspects of our business may become financially unstable or may not be sufficient to cover any or all of our losses and may not continue to be available to us on acceptable terms, or at all.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">47</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are dependent upon our own or third-party information technology systems, infrastructure and data, including mobile
        technologies, to operate our business.&#160;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.&#160;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.&#160;Cyber-attacks are increasing in their frequency, sophistication and intensity. 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.&#160;Our business partners face similar risks and any security breach of their systems could adversely affect our security posture.&#160;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/or state
        breach notification laws and foreign law equivalents, subject us to mandatory 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/or 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.&#160;While we have invested, and continue to invest, in the protection of our data and information technology infrastructure, there can be no
        assurance that our efforts will prevent service interruptions, or identify breaches in our systems, that could adversely affect our business and operations and/or result in the loss of critical or sensitive information, which could result in
        financial, legal, business or reputational harm to us.&#160;In addition, our liability insurance may not be sufficient in type or amount to cover us against claims related to security breaches, cyber-attacks and other related breaches.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 1B. Unresolved Staff Comments</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Not applicable.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:c1c452f3-777c-4a81-81dd-ad5ce5089387">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 2. Properties</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As of February 20, 2019, we occupied the following properties:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z38fdba9fb0a946c18919ec26f3a69380" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 19.92%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Property Description</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top;">&#160;</td>
          <td style="width: 12.68%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Location</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top;">&#160;</td>
          <td style="width: 9.79%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Square</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Footage</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top;">&#160;</td>
          <td style="width: 10.42%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Owned</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">or Leased</font></div>
          </td>
          <td style="width: 2%; vertical-align: top;">&#160;</td>
          <td style="width: 14.63%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Initial Lease</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Term End Date</font></div>
          </td>
          <td style="width: 2%; vertical-align: top;">&#160;</td>
          <td style="width: 22.44%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Lease</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Extension Options</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 19.92%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis laboratory and office space facility</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 12.68%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Carlsbad, CA</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 9.79%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">176,000</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 10.42%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Owned</font></div>
          </td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 14.63%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 22.44%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 19.92%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis manufacturing facility</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 12.68%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Carlsbad, CA</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 9.79%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,700</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 10.42%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Owned</font></div>
          </td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 14.63%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 22.44%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 19.92%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis manufacturing support facility</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 12.68%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Carlsbad, CA</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 9.79%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">25,800</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 10.42%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Leased</font></div>
          </td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 14.63%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2021</font></div>
          </td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 22.44%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Two, five-year options to extend</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 19.92%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea office space facility</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 12.68%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Boston, MA</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 9.79%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,175</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 10.42%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Leased</font></div>
          </td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 14.63%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2028</font></div>
          </td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 22.44%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">One, five-year option to extend</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 19.92%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea office and Ionis storage space facility</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 12.68%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Carlsbad, CA</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 9.79%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,700</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 10.42%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Leased</font></div>
          </td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 14.63%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div>
          </td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 22.44%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">One, five-year option to extend</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 19.92%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 12.68%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 9.79%; vertical-align: bottom; border-bottom: 4px double rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">279,375</font></div>
          </td>
          <td style="width: 2.04%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 10.42%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 14.63%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 22.44%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:3d69979a-0c34-4d2d-ab58-b0038648b22a">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 3. Legal Proceedings</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Gilead Litigation</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In August 2013, Gilead Sciences Inc. filed a suit in the U.S. District Court of Northern District of California related to
        U.S. Patent Nos. 7,105,499 and 8,481,712, which are jointly owned by Merck Sharp &amp; Dohme Corp. and Ionis Pharmaceuticals, Inc.&#160;In the suit Gilead asked the court to determine that Gilead&#8217;s activities do not infringe any valid claim of the named
        patents and that the patents are not valid. We and Merck Sharp &amp; Dohme Corp. filed our answer denying Gilead&#8217;s noninfringement and invalidity contentions, contending that Gilead&#8217;s commercial sale and offer for sale of sofosbuvir prior to the
        expiration of the &#8216;499 and &#8216;712 patents infringes those patents, and requesting monetary damages to compensate for such infringement. In the trial for this case held in March 2016, the jury upheld all 10 of the asserted claims of the
        patents-in-suit. The jury then decided that we and Merck are entitled to <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">four percent of $5 </font>billion in past sales of sofosbuvir. Gilead has stated it would appeal
        the jury&#8217;s finding of validity. In the meantime, Gilead asserted <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">two </font>additional non-jury defenses: waiver and unclean hands. Although the judge rejected the
        waiver defense, she granted Gilead&#8217;s motion claiming that the patents are unenforceable against it under the doctrine of unclean hands. We believe this ruling is contrary to the relevant law and the facts of the case. Accordingly, in July 2016,
        together with Merck we appealed the decision to the Court of Appeals for the Federal Circuit. Gilead cross-appealed on the issue of validity. In April 2018, the Court of Appeals issued its ruling affirming the District Court&#8217;s finding of
        unenforceability based on unclean hands.&#160;Having upheld the ruling that the patents are unenforceable against Gilead, the court did not reach the question of validity. In September 2018, we filed a petition requesting a hearing before the Supreme
        Court, asserting that it was improper for the trial court to overturn the jury verdict on the basis of the equitable defense of unclean hands. In January 2019, the Supreme Court denied our petition. Under our agreement with Merck, Merck is
        responsible for the costs of this suit.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">48</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 4. Mine Safety Disclosures</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Not applicable.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:d2e8aafe-2b92-4ac6-9042-773a4632aefa">
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">PART II</div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 5. Market for Registrant</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our common stock is traded publicly through The Nasdaq Global Select Market under the symbol &#8220;IONS.&#8221; As of February 20,
        2019, there were approximately 541 stockholders of record of our common stock. Because many of our shares are held by brokers and other institutions on behalf of stockholders, we are unable to estimate the total number of stockholders represented
        by these record holders.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have never paid dividends and do not anticipate paying any dividends in the foreseeable future.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Set forth below is a table and chart comparing the total return on an indexed basis of $100 invested on December&#160;31, 2013
        in our common stock, the Nasdaq Composite Index (total return) and the Nasdaq Biotechnology Index. The total return assumes reinvestment of dividends.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Performance Graph (1)</font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><img width="564" height="441" src="image16.jpg"></div>
    <div><br>
    </div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Pharmaceuticals,&#160;Inc.</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">154.97</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">155.45</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120.06</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">126.26</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">135.69</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Nasdaq Composite Index</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">100.00</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">114.62</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">122.81</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">133.19</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">172.11</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">165.84</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Nasdaq Biotechnology Index</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">100.00</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">131.71</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">140.56</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112.25</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">133.67</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">121.24</font></div>
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">This section is not &#8220;soliciting material,&#8221; is not deemed &#8220;filed&#8221; with the SEC, is not subject to the liabilities of Section&#160;18 of the Exchange Act and is not
                    to be incorporated by reference in any of our filings under the Securities Act or the Exchange Act, whether made before or after the date hereof and irrespective of any general incorporation language in any such filing.</font></div>
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  <div id="TRGRSegment:a1dcf042-8d42-475c-a43b-8b656512e663">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 6. Selected Financial Data</div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">This selected financial data should be read in conjunction with our audited consolidated financial statements and
        accompanying notes and Management&#8217;s Discussion and Analysis of Financial Condition and Results of Operations included elsewhere in this Annual Report on Form 10-K. Our historical consolidated financial information may not be indicative of our
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="18" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">599.7</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">514.2</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">372.8</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">283.7</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">214.2</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research, development and patent expenses</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">414.6</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">374.6</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">344.3</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">322.3</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">241.8</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selling, general and administrative expenses</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">244.6</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108.5</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48.6</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">37.2</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">20.1</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) attributable to Ionis Pharmaceuticals,&#160;Inc. common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">273.7</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.3</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60.4</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(88.3</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(39.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.09</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.15</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.50</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.74</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.33</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.15</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares used in computing basic net income (loss) per share</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">132.3</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">117.7</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares used in computing diluted net income (loss) per share</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">134.1</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120.9</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">117.7</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="18" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As of December 31,</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2015</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2014</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Consolidated Balance Sheet Data:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash, cash equivalents and short-term investments</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,084.1</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,022.7</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">665.2</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">779.2</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">728.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Working capital</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,927.6</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">925.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">664.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">688.1</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">721.3</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total assets</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,667.8</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,322.8</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">912.5</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">947.9</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">946.5</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term debt and other obligations, less current portion</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,200.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">713.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">679.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">598.2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">588.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accumulated deficit</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(967.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,241.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,181.4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,094.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,006.6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Stockholders&#8217; equity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,187.2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">365.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">99.6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">200.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">257.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="background-color: #FFFFFF;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z145879420b144faba627c04c51e407d9" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></div>
              </td>
              <td style="width: auto; vertical-align: top;">
                <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Reflects the impact of our adoption of the new
                      revenue recognition accounting standard in 2018 (Topic 606). For additional details about our adoption of Topic 606, see Note 1, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization





                      and Significant Accounting Policies</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">,</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in the
                      Notes to the Consolidated Financial Statements. This change is not reflected in our consolidated statement of operations data for 2015 or 2014 or in our consolidated balance sheet data for 2016, 2015, or 2014.</font></font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:5c9459fd-1937-44ec-90d5-d88b5cc97115">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 7. Management</font>&#8217;<font style="font-size: 10pt;
        font-family: 'Times New Roman', Times, serif; font-weight: bold;">s Discussion and Analysis of Financial Condition and Results of Operations</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">This financial review presents our operating results for each of the three years in the period ended December 31, 2018,
        and our financial condition at December 31, 2018. Except for the historical information contained herein, the following discussion contains forward-looking statements that are subject to known and unknown risks, uncertainties and other factors that
        may cause our actual results to differ materially from those expressed or implied by such forward-looking statements. We discuss such risks, uncertainties and other factors throughout this report and specifically under Item&#160;1A of Part&#160;I of this
        report, &#8220;Risk Factors.&#8221; In addition, the following review should be read in conjunction with the information presented in our consolidated financial statements and the related notes to our consolidated financial statements as indexed on page F-1.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Overview</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are a leader in discovering and developing RNA-targeted therapeutics with sustained and growing revenues. We have
        created an efficient and broadly applicable drug discovery platform leveraging our expertise in antisense oligonucleotide therapeutics that we believe has fundamentally changed medicine and transformed the lives of people with devastating and often
        deadly diseases. Our large, diverse and advanced pipeline of over 40 first-in-class and/or best-in-class medicines addresses diseases across a broad range of therapeutic areas, targeting small, medium and large patient populations.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have two commercial medicines approved in major markets around the world, SPINRAZA and TEGSEDI. We have at least four
        medicines that have entered pivotal studies or have the potential to begin pivotal studies this year, and another six medicines that could start pivotal studies in 2020. These medicines, along with the more than 30 additional medicines in our
        pipeline, represent multiple potential drivers of value for years to come. We believe our efficient drug discovery platform, coupled with our innovation-centric business model, provides us with the flexibility to determine the optimal development
        and commercialization strategy to maximize the commercial opportunity for each of our medicines and ensure that we continue to produce transformative medicines for patients who need them. We believe we are positioned to drive substantial value for
        patients and shareholders.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As of January 2019, SPINRAZA was approved in over 40 countries around the world, and our partner Biogen, who is
        responsible for global SPINRAZA commercial activities, reported that more than 6,600 patients are now on SPINRAZA therapy. In addition, Biogen plans to continue to pursue regulatory filings in additional countries. Biogen reported 2018 annual sales
        of SPINRAZA of more than $1.7 billion, and we earned $238 million in commercial revenues from royalties on sales of SPINRAZA. SPINRAZA is the first and only approved medicine for the treatment of SMA. SPINRAZA is the established standard-of-care
        for all people with this progressive, debilitating and often fatal genetic disease. In November 2018, SPINRAZA was recognized with the 2018 International Prix Galien award as Best Biotechnology Product. This prestigious honor marks the seventh Prix
        Galien award for SPINRAZA.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">50</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI, a once weekly, self-administered subcutaneous medicine, was approved in 2018 in the U.S., EU and Canada for the
        treatment of polyneuropathy caused by hATTR in adult patients. hATTR is a debilitating, progressive, and fatal disease. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea, our majority-owned affiliate focused on
          developing and commercializing medicines to treat patients with rare and serious diseases, </font>launched TEGSEDI globally in late 2018. In the fourth quarter of 2018, we earned more than $2 million in TEGSEDI product sales. Akcea has an
        exclusive license agreement with PTC to commercialize TEGSEDI in Latin America. In January 2019, PTC filed an application for regulatory approval in Brazil with ANVISA, the Brazilian regulatory authority. ANVISA granted priority review for TEGSEDI.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We and Akcea are preparing to commercialize
          WAYLIVRA in the EU. The CHMP of the EMA adopted a positive opinion recommending conditional marketing authorization for WAYLIVRA as an adjunct to diet in adult patients with genetically confirmed&#160; FCS who are at high risk for pancreatitis, in
          whom response to diet and triglyceride lowering therapy has been inadequate. The positive opinion will now be referred to the EC which grants marketing authorization for medicines in the EU, as well as to European Economic Area members Iceland,
          Liechtenstein and Norway. With this positive opinion, and, pending adoption of the positive opinion by the EC, Akcea plans to leverage its existing commercial infrastructure in Europe to market WAYLIVRA. </font>Akcea is continuing to conduct
        open-label extension and early access programs.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> We are also focused on regulatory discussions in the U.S. We are developing WAYLIVRA to treat FPL a second severe and rare,
          genetically defined disease. FCS and FPL are orphan diseases characterized by severely high triglyceride levels that result in severe, daily symptoms and a high risk of life-threatening pancreatitis.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In addition to commercializing TEGSEDI and preparing to commercialize WAYLIVRA, Akcea is developing four other
        clinical-stage medicines: AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>(TQJ230), AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AKCEA-TTR-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, </font>each of which could potentially treat multiple patient populations. Moving these drugs into Akcea allows us to retain substantial value from these medicines and
        ensures our core focus remains on innovation.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> As of February 2019, we owned approximately 75 percent of Akcea.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are continuously advancing our technology and pipeline to provide the most value to patients. We have a pipeline of
        over 40 medicines that, like SPINRAZA and TEGSEDI, have the potential to transform the treatment of diseases with no adequate treatment today. These medicines range from treatments for rare diseases with small patient populations to more common
        diseases afflicting millions of patients. Our pipeline covers a broad spectrum of therapeutic areas, such as cardiometabolic diseases, neurodegenerative diseases, cancer, severe and rare diseases and others. We believe our large and diverse
        pipeline contains many near-, mid- and longer-term growth drivers for the company.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our pipeline includes at least 10 potentially transformative medicines anticipated to enter pivotal clinical studies in
        the next two years. We anticipate at least four of these medicines will enter pivotal studies this year including: AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, AKCEA-TTR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> (RG6042) and IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. Roche recently
        initiated a Phase 3 study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>for HD. We believe each of these medicines is a first-in-class and/or best-in-class medicine with the potential to deliver significant value to patients and shareholders. We anticipate that the
        data from these pivotal studies, if positive, will support global regulatory filings for each medicine.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The depth of our knowledge and expertise with
          antisense technology together with our strong financial position provides us the flexibility to partner our medicines at what we believe is the optimal time to maximize the near-term, mid-term and long-term value of our medicines. </font>We have
        a distinct partnering strategy based on each specific medicine and the expertise and resources we and our potential partners may bring to a collaboration. We may develop and commercialize some medicines through affiliates. In general, these are
        medicines, like TEGSEDI, that can benefit from our internal expertise and infrastructure, have manageable development costs and have the potential for initial rare disease indications. For other medicines, <font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">we may establish collaborations to advance the medicine. We have alliances with a cadre of leading global pharmaceutical companies that are working alongside us in developing our medicines, advancing
          our technology, preparing to commercialize our medicines and selling our medicines. Our partners include the following companies, among others: AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis and Roche. Our partners bring resources and
          expertise that augment and build upon our internal capabilities.</font> We have the potential to earn over $20 billion in future milestone payments and licensing fees from our existing partnerships.</font></div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">51</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Financial Highlights</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">The following is a summary of our financial results (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z1ab6346f2974402d9cb2bc1ad68ebd82" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">599,674</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">514,179</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">372,776</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total operating expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">661,046</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">483,132</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">392,936</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income (loss) from operations</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(61,372</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">31,047</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(20,160</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">214,985</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(10,783</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -8.85pt; margin-left: 8.85pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">273,741</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">346</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash, cash equivalents and short-term investments</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,084,072</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,022,715</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">665,223</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our revenue for 2018 was $599.7 million and increased significantly compared to 2017 and 2016, primarily from increased
        commercial revenue from SPINRAZA royalties.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our operating expenses for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2018</font> were
        $661.0 million and continued to increase year-over-year. The increase in operating expenses was primarily due to higher SG&amp;A expenses as we prepared to commercialize <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI





          and WAYLIVRA</font>. Our SG&amp;A expenses also increased because of fees we owed under our in-licensing agreements related to SPINRAZA. We earn tiered royalties on annual SPINRAZA sales and pay nominal fixed third-party royalties that are not
        tiered. R&amp;D expenses accounted for a smaller portion of the increase in operating expenses.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">52</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The increase in 2018 net income attributable to Ionis&#8217; common stockholders was primarily due to increases in revenue and
        the income tax benefit we recognized in the fourth quarter of 2018. Our tax benefit increased significantly in 2018 primarily due to a one-time non-cash tax benefit related to Ionis&#8217; stand-alone deferred federal income tax assets. In the fourth
        quarter of 2018, we released a large portion of our valuation allowance associated with our deferred tax assets. As a result of our strong financial performance over the past few years and our outlook regarding the continued growth of our business,
        we determined that it was more likely than not that we would be able to realize most of our deferred income tax assets we have accumulated to offset future taxable income.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">During 2018 we received more than $1.5 billion in payments from our partners, including $1 billion from Biogen for our
        2018 strategic neurology collaboration. This is compared to $580 million received in 2017 and $190 million received in 2016. We believe our strong financial position should enable us to continue to execute on our corporate goals throughout 2019 and
        beyond.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Business Segments</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have two operating segments, our Ionis
          Core segment and Akcea Therapeutics, our majority-owned affiliate. Akcea is </font>a biopharmaceutical company focused on developing and commercializing medicines to treat patients with rare and serious diseases<font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">. We provide segment financial information and results for our Ionis Core segment and our Akcea Therapeutics segment based on the segregation of revenues and expenses that our chief decision maker
          reviews to assess operating performance and to make operating decisions. We allocate a portion of Ionis&#8217; development, R&amp;D support and general and administrative expenses to Akcea for work Ionis performs on behalf of Akcea.</font></font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:b7e70641-9b11-4a6b-9ac3-44a37029a0fd">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Critical Accounting Policies</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the United
        States. As such, we make certain estimates, judgments and assumptions that we believe are reasonable, based upon the information available to us. These judgments involve making estimates about the effect of matters that are inherently uncertain and
        may significantly impact our quarterly or annual results of operations and financial condition. Each quarter, our senior management reviews the development, selection and disclosure of such estimates with the audit committee of our board of
        directors. In the following paragraphs, we describe the specific risks associated with these critical accounting policies and we caution that future events rarely develop exactly as one may expect, and that best estimates may require adjustment.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following are our significant accounting policies, which we believe are the most critical to aid in fully
        understanding and evaluating our reported financial results:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z893d8a885c2243f9a54d6fcd7ceebe0f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Assessing the propriety of revenue recognition and associated deferred revenue;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z3edce2f4c3cf41b18436dde9e6687505" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Valuing premiums received under our collaborations;<font style="font-size: 10pt; font-family: Symbol;"></font></font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z015f203210b8446390f0666ed47bcb6f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Determining the proper valuation of investments in marketable securities;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zac90cb97dfbe490da72894ac0e2e173e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Determining the appropriate cost estimates for unbilled preclinical studies and clinical development activities; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z4527914bc7ee4fc1a694359740e256a2" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: Symbol;"></font>ncome taxes.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Descriptions of these critical accounting policies follow.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Revenue Recognition</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Adoption of New Revenue Recognition
            Accounting Standard (Topic 606)</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In May 2014, the FASB issued accounting guidance on the recognition of revenue from customers. <font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">This guidance supersedes the revenue recognition requirements we previously followed in Accounting Standards Codification, or ASC, Topic 605, </font><font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif; font-style: italic;">Revenue Recognition</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, or Topic 605, and created a new Topic 606, </font><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif; font-style: italic;">Revenue from Contracts with Customers</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, or Topic 606. </font>Under Topic 606, an entity will
        recognize revenue when it transfers control of promised goods or services to customers in an amount that reflects what the entity expects to receive in exchange for the goods or services. Further, an entity will recognize revenue upon satisfying
        the performance obligation(s) under the related contract. We adopted Topic 606 on January 1, 2018 under the full retrospective approach, which required us to revise our prior period revenue. Under Topic 606, we were required to review all of our
        ongoing collaboration agreements in which we recognized revenue after January 1, 2016. We were required to assess what our revenue would have been for the period from January 1, 2016 to December 31, 2017 under Topic 606. As a result of this
        analysis, we determined that the cumulative revenue we would have recognized under Topic 606 decreased by $86.1 million. We recorded this amount as a cumulative adjustment to our accumulated deficit as of January 1, 2016 on our revised statement of
        stockholders&#8217; equity. We have labeled our prior period financial statements &#8220;as revised&#8221; to indicate the change required under the accounting rules.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following tables summarize the adjustments we were required to make to amounts we originally reported in 2017 and 2016
        to adopt Topic 606 (in thousands, except per share amounts):</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Consolidated Balance Sheet</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zf712122a75a64d0f82dce495230081a7" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">At December 31, 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 605</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current portion of deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">106,465</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,871</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">125,336</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term portion of deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,708</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">35,318</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,026</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accumulated deficit</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,187,398</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(53,636</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,241,034</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;&#160;&#160;Noncontrolling interest in Akcea Therapeutics, Inc.</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">87,847</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,267</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">418,719</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">365,280</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
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            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Revenue:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112,540</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112,540</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Licensing and other royalty revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,519</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2,045</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,474</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total commercial revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">122,059</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2,045</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120,014</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research and development revenue under collaborative agreements</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">385,607</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,558</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">394,165</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">507,666</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,513</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">514,179</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24,534</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,513</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">31,047</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(17,296</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,513</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(10,783</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,970</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,316</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">346</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income per share, basic and diluted</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.08</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.07</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.15</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">883</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">883</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Licensing and other royalty revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">19,839</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,045</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,884</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total commercial revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">20,722</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,767</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">325,898</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24,111</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">350,009</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">346,620</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,156</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">372,776</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income (loss) from operations</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(46,316</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(20,160</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(86,556</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(86,556</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) per share, basic and diluted</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.72</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.22</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.50</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Consolidated Statements of Cash Flows</font></div>
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    <table cellspacing="0" cellpadding="0" id="z8028c6999f4945ed87d53f177d39c223" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 605</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(17,296</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,513</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(10,783</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -27.15pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">36,695</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(6,513</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,182</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents at beginning of period</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,685</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,685</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents at end of period</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">129,630</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">129,630</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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    <table cellspacing="0" cellpadding="0" id="z417036c608b44276a7d283133c15593f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 605</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(86,556</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -27.15pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(59,150</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(26,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(85,306</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents at beginning of period</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">128,797</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">128,797</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents at end of period</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,685</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,685</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div style="text-align: justify; text-indent: 36pt;"><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under Topic 606, compared to Topic 605, our total revenue increased $6.5 million for <font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">2017</font> and $26.2 million for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2016</font>. The change in our revenue was primarily due to:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zcaf426108b1e4bfea83b323fb517385b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>A change in how we recognize milestone payments:</u></font> Topic 606 requires
                    us to amortize more of the milestone payments we achieve, rather than recognizing the milestone payments in full in the period in which we achieved the milestone event as we did under Topic 605. This change resulted in an increase in
                    R&amp;D revenue recognized for 2017 and 2016 of $23.6 million and $24.1 million, respectively.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">54</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z2ee4474f1eec475e968442affc3e5a1a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>A change in how we calculate revenue for payments we are recognizing into
                        revenue over time:</u></font> Under Topic 605, we amortized payments into revenue evenly over the period of our obligations. When we made a change to our estimated completion period, we recognized that change on a prospective basis.
                    Under Topic 606, we use an input method to determine the amount we amortize each reporting period. Each period, we review our &#8220;inputs&#8221; such as our level of effort expended, including the time we estimate it will take us to complete the
                    activities, or costs incurred relative to the total expected inputs to satisfy the performance obligation. For certain collaborations, such as Bayer, Janssen and Novartis, the input method resulted in a change to the revenue we had
                    previously recognized using a straight-line amortization method. This change resulted in a decrease in our R&amp;D revenue of $15.1 million for 2017. This change did not result in an impact to our 2016 R&amp;D revenue.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our updated revenue recognition policy reflecting Topic 606 is as follows:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Our Revenue Sources</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting
        the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing
        revenue, we include the amounts in deferred revenue on our consolidated balance sheet.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as
        commercial revenue future sales milestone payments and royalties we earn under our partnerships.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Commercial Revenue: TEGSEDI product sales, net</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We began adding product sales from TEGSEDI to
          our commercial revenue in the fourth quarter of 2018. </font>In the U.S., TEGSEDI is distributed through an exclusive distribution agreement with a third-party logistics company, or 3PL, that takes title to TEGSEDI. The 3PL is our sole customer
        in the U.S. The 3PL then distributes TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distribute TEGSEDI to health care providers and patients. In Germany, TEGSEDI is distributed
        through a non-exclusive distribution model with a 3PL that takes title to TEGSEDI. The 3PL is our sole customer in Germany. The 3PL in Germany then distributes TEGSEDI to hospitals and pharmacies.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Research and development revenue under collaborative agreements</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis.
        Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;D, services, and manufacturing services.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our collaboration agreements are detailed in Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements.</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>Under each collaboration note we discuss our specific
        revenue recognition conclusions, including our significant performance obligations under each collaboration.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Steps to Recognize Revenue</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use a five step process to determine the amount of revenue we should recognize and when we should recognize it. The
        five step process is as follows:</font></div>
    <div><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zb092397203d046fa88b8db8e2cf0657a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">1.</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Identify the contract</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met
        each of the following criteria:</font></div>
    <div><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="ze0c17a9092884f60b9ed93b1d4861925" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We and our partner approved the contract and we are both committed to perform our obligations;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z4e5e058c6c6641e7a657fac596f72828" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have identified our rights, our partner&#8217;s rights and the payment terms;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z5e489cbc1c3d45cfbbd504f3c28a687b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a
                    result of the contract; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z46d6eb8980854ec58b881b2fd65980de" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe collectability is probable.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="margin-bottom: 10pt;"><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z473d9705cae8484987da24b47bcd0b38" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">2.</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Identify the performance obligations</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We next identify the distinct goods and services we are required to provide under the contract. Accounting rules refer to
        these as our performance obligations. We typically have only one performance obligation at the inception of a contract, which is to perform R&amp;D services.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">55</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Often times we enter into a collaboration agreement in which we provide our partner with an option to license a medicine
        in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We evaluate whether these options are material rights at the
        inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the options we grant to license a medicine in the future or to provide
        additional goods and services as requested by our partner are not material rights. These items are contingent upon future events that may not occur. When a partner exercises its option to license a medicine or requests additional goods or services,
        then we identify a new performance obligation for that item.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the
        license and we do not have any additional performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zab13bbdeaaa74d9cac095f22b636fd7f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">3.</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Determine the transaction price</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the
        collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone
        payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because
        the payments are not probable. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most
        likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone
        payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the
        majority of our milestone payments are contingent upon events that are not within our control and are usually based on scientific progress. For example, in January 2019 we earned a $35 million milestone payment from Roche when it dosed the first
        patient in the Phase 3 study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.&#160; At December 31, 2018, we determined it was not probable that we could earn this milestone payment.&#160;As such, we did not recognize any revenue associated with it in 2018.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z62f6072f7a274f46a80a06cf00a4f5e9" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">4.</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Allocate the transaction price</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction
        price to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the
        transaction price to each performance obligation based on the relative stand-alone selling price.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price
        for collaborations in which we deliver a license at the start of an agreement. We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the
        amount of income, net of taxes, for the license. We then discount the projected income to present value. The significant inputs we use to determine the projected income of a license could include:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z43f84326b0c844f094ef65b4781b13d4" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Estimated future product sales;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="ze1c3ad085d9147a2b4c2b32e1fb77cd6" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Estimated royalties on future product sales;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z388897e3f75e4ac9b0dbf4fe6b18e22d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Contractual milestone payments;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zfb51970da6414c798abf889f8478a26f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expenses we expect to incur;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z774e92b9ff0543e2852f62cf30961b68" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income taxes; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zba35439ba9f142588812d199c389749f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A discount rate.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We typically estimate the selling price of R&amp;D services by using our internal estimates of the cost to perform the
        specific services. The significant inputs we use to determine the selling price of our R&amp;D services include:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zffe8746d113b4c4fb8b70ce2c909877d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The number of internal hours we estimate we will spend performing these services;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z26a3b2d712d34055ae5f89869a39d377" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of work we will perform;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zcd496257036c4b9f94d4012e7c0fc866" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of work that we will contract with third parties to perform; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zbd1533e0b39a424db984186876a9ffc0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of API we will use.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For purposes of determining the stand-alone selling price of the R&amp;D services we perform and the API we will deliver,
        accounting guidance requires us to include a markup for a reasonable profit margin.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone
        selling prices.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zabcb707232ce4bd89fc294aa20766120" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">5.</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Recognize revenue</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are
        executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;D services. We recognize revenue at a point in time when our partner receives full use
        of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">56</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For R&amp;D services that we recognize over time, we measure our progress using an input method. The input methods we use
        are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a
        given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach
        requires us to make numerous estimates and use significant judgement. If our estimates or judgements <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">change over the course of the collaboration, they may affect the
          timing and amount of revenue that we recognize in the current and future periods.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following are examples of when we typically recognize revenue based on the types of payments we receive.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Commercial Revenue:
            SPINRAZA royalties and Licensing and other royalty revenue</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize royalty revenue in the period in
          which the counterparty sells the related product, which in certain cases may require us to estimate our royalty revenue. </font>We recognize royalties from SPINRAZA sales in the period Biogen records the sale of SPINRAZA. Our accounting for
        SPINRAZA royalties did not change as a result of adopting Topic 606.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Commercial Revenue:
            TEGSEDI Product Sales, net</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize TEGSEDI product sales in the
          period </font>when our customer obtains control of TEGSEDI, which occurs at a point in time upon transfer of title to the customer. We classify payments to customers or other parties in the distribution channel for services that are distinct and
        priced at fair value as selling, general and administrative expenses in our consolidated statements of operations. Otherwise payments to customers or other parties in the distribution channel that do not meet those criteria are classified as a
        reduction of revenue, as discussed further below. We exclude from revenues, taxes collected from customers relating to product sales and remitted to governmental authorities.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Reserves for TEGSEDI Product Sales</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We record TEGSEDI product sales at our net sales price, or transaction price. We include in our transaction price
        estimated reserves for discounts, returns, chargebacks, rebates, co-pay assistance and other allowances that we offer within contracts between us and our customers, wholesalers, health care providers and other indirect customers. We estimate our
        reserves using the amounts we have earned or what we can claim on the associated sales. We classify our reserves as reductions of accounts receivable when the amount is payable to our customer or a current liability when the amount is payable to a
        party other than our customer in our consolidated balance sheet. In certain cases, our estimates include a range of possible outcomes that are probability-weighted for relevant factors such as our historical experience, current contractual and
        statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflect our best estimates under the terms of our respective contracts. When calculating our
        reserves and related product sales, we only recognize amounts to the extent that we consider it probable that we would not have to reverse in a future period a significant amount of the cumulative sales we previously recognized. The actual amounts
        we receive may ultimately differ from our reserve estimates. If actual amounts in the future vary from our estimates, we will adjust these estimates, which would affect our net TEGSEDI product sales in the respective period.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; margin-bottom: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following are the components of variable consideration related to TEGSEDI product sales:</font></div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Chargebacks: </font>In
        the U.S., we estimate obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer
        charges us for the difference between what it pays for the product and the selling price to the qualified healthcare providers. We record reserves for these chargebacks related to TEGSEDI product sales to our U.S. customer during the reporting
        period. We also estimate the amount of product remaining in the distribution channel inventory at the end of the reporting period that we expect our customer to sell to wholesalers in future periods.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Government rebates</font>:
        We are subject to discount obligations under government programs, including Medicaid programs and Medicare in the U.S. We estimate Medicaid and Medicare rebates based on a range of possible outcomes that are probability-weighted for the estimated
        payer mix. We record these reserves as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales in the same period we recognize the related sale. For Medicare rebates, we also estimate
        the number of patients in the prescription drug coverage gap for whom we will owe an additional liability under the Medicare Part D program. On a quarterly basis, we update our estimates and record any adjustments in the period that we identify the
        adjustments. In Germany, pharmaceutical companies must grant a specified rebate percentage to the German government. We include this rebate in the same period we recognize the related TEGSEDI product sales, resulting in a reduction of product
        sales.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Trade discounts and
          allowances: </font>We provide customary invoice discounts on TEGSEDI product sales to our U.S. customer for prompt payment. We record this discount as a reduction of TEGSEDI product sales in the period in which we recognize the related product
        revenue. In addition, we receive and pay for various distribution services from our U.S. customer and wholesalers in our U.S. distribution channel. For services we receive that are either not distinct from the sale of TEGSEDI or for which we cannot
        reasonably estimate the fair value, we classify such fees as a reduction of TEGSEDI product sales.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Product Returns: </font>Our





        U.S. customer has return rights and the wholesalers have limited return rights primarily related to the expiration date of the TEGSEDI product. We estimate the amount of TEGSEDI product sales that our customer may return. We record our return
        estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale. Based on our distribution model for TEGSEDI, contractual
        inventory limits with our customer and wholesalers and the price of TEGSEDI, we believe we will have minimal returns. Our customer in Germany only takes title to the product once it receives an order from a hospital or pharmacy and therefore does
        not maintain any inventory of TEGSEDI, as such we do not estimate returns in Germany.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">57</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Other incentives:</font>
        In the U.S., we estimate reserves for other incentives including co-payment assistance we provide to patients with commercial insurance who have coverage and reside in states that allow co-payment assistance. We record a reserve for the amount we
        estimate we will pay for co-payment assistance. We base our reserve on the number of estimated claims and our estimate of the cost per claim related to TEGSEDI product sales that we have recognized as revenue. We record our other incentive reserve
        estimates as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Research and development
            revenue under collaboration agreements:</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Upfront Payments</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">When we enter into a collaboration agreement with an upfront payment, we typically record the entire upfront payment as
        deferred revenue if our only performance obligation is for R&amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&amp;D services. For example, under our new <font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">collaboration agreement with Roche to</font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> develop IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;for the treatment of complement-mediated diseases</font>, we received a $75 million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our
        single performance obligation, R&amp;D services. We are amortizing the $75 million upfront payment using an input method over the estimated period of time we are providing R&amp;D services. Refer to <font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;">Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font>, for further discussion. Under Topic
        605, we amortized upfront payments evenly over the period of our obligation.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Milestone Payments</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are required to include additional consideration in the transaction price when it is probable. We typically include
        milestone payments for R&amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because there is considerable uncertainty in the research and development processes that trigger
        these payments under our collaboration agreements. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales based milestone payments in the
        period we achieve the milestone under the sales-based royalty exception allowed under accounting rules.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For
        example, in the third quarter of 2017, we initiated a Phase 1/2a clinical study of IONIS-MAPT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>in patients with mild Alzheimer&#8217;s disease. We earned a $10 million milestone payment from Biogen related to the initiation of this study.
        Under Topic 606, we added this payment to the transaction price and allocated it to our R&amp;D services performance obligation. We are recognizing revenue from this milestone payment over our estimated period of performance. Under Topic 605, this
        milestone payment was recognized in full in the third quarter of 2017, which was the period in which we achieved the milestone event.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Conversely, we recognize in full those milestone payments that we earn based on our partners&#8217; activities when our partner
        achieves the milestone event. For example, in the third quarter of 2018, we recognized a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of IONIS-AZ4-2.5-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. <font style="font-size: 10pt; font-family: 'Times
          New Roman', Times, serif;">We concluded that the milestone payment was not related to our R&amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any
          performance obligations related to this milestone payment. </font>Our revenue recognition of milestone payments we earn based on our partners&#8217; activities did not change as a result of adopting Topic 606.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>License Fees</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We generally recognize as revenue the total
          amount we determine to be the stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the
          license after delivery. </font>For example, in the fourth quarter of 2018, we earned a $35 million license fee when Biogen licensed IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> from us. Our recognition of license fees did not change as a result of adopting Topic
        606.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Amendments to Agreements</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items
        to determine the accounting for the amendment:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z88c6ff84ccdb4e1d946302e1a4828aff" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z1f575f6da56c47b9a12aa1b525eb9549" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If the goods and/or services are at a stand-alone selling price.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original
        agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and at their stand-alone selling price, we then assess whether the remaining goods or
        services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from
        the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated
        revenue as a cumulative adjustment.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">58</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, in May 2015, we entered into an
          exclusive license agreement with Bayer to develop and commercialize IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for the prevention of thrombosis. As part of the agreement, Bayer paid
          us a $100 million upfront payment. At the onset of the agreement, we were responsible for completing a Phase 2 study of IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in people with
          end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif;"> and to initiate development of IONIS-FXI-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also
          eligible to receive milestone payments and tiered royalties on gross margins of IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and IONIS-FXI-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of IONIS-FXI-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, to provide R&amp;D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. </font>Refer to <font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font>, for further
        discussion <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">of our accounting treatment for our Bayer collaboration. </font>Our allocation of the consideration we received for the Bayer amendment did not change as a
        result of adopting Topic 606. However, the method in which we are recognizing revenue related to our R&amp;D services performance obligation did change. We are amortizing revenue related to our R&amp;D services performance obligation using the
        input method under Topic 606.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Multiple Agreements</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such
        agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the
        agreements:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z3f14259d32f742da8fff2fb4e10d22a2" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the agreements were negotiated together with a single objective;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z43eb7d6716204e83ba17da2220f85193" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z14e29a79572042fd85b4a39da3188ea0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the goods and/or services promised under the agreements are a single performance obligation.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance
        requires us to account for them as a combined arrangement.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: a new
        strategic neurology collaboration agreement and a SPA. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them.
          We considered that the agreements were negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis. Refer to Note
          6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">
          for further discussion of the accounting treatment for the 2018 strategic neurology collaboration with Biogen.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Deferred Revenue</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are often entitled to bill our customers
          and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table summarizes the adjustments we were required to make to our deferred revenue amounts to adopt Topic 606
        (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zf580bc93defc4619862ef25fd7c0f952" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">At December 31, 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 605</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current portion of deferred revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">106,465</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,871</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">125,336</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term portion of deferred revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,708</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">35,318</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,026</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total deferred revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">179,173</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">54,189</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">233,362</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our deferred revenue balance increased $54.2 million at December 31, 2017 under Topic 606, compared to Topic 605. The
        increase was primarily related to the change in the accounting for certain milestone payments and the way in which we amortize payments. Under Topic 605, we previously recognized the majority of the milestone payments we earned in the period we
        achieved the milestone event, which did not impact our deferred revenue balance. Under Topic 606 we are now amortizing more milestone payments over the period of our performance obligation, which adds to our deferred revenue balance. Additionally,
        under Topic 605 we amortized payments evenly over the period of our obligation. Under Topic 606, we use an input method to determine the amount we amortize each reporting period. The increase in deferred revenue relates to agreements with the
        following partners:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zf04a343437cf46c5b9bdeb29b8b2a488" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$24.2 million from Biogen;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z17c8b662aec34543877b3b8984004a22" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$15.9 million from AstraZeneca;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z876be037a6044af0b973753ec13221db" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$11.8 million from Novartis; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z737167e0acf948c6bdb7ed8a49dc8030" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$ 2.3 million from other partners.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Valuation of Premiums under our Collaborations</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In conjunction with our collaboration
          agreements we have sold stock at a premium to our partners, including under our 2018 strategic neurology collaboration with Biogen and with Novartis in 2017. See further discussion about our valuation of the potential premium in our Fair Value
          Measurements policy in Note 1, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant Accounting Policies</font><font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;">, in the Notes to the Consolidated Financial Statements.</font></font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">59</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Biogen Premium</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the second
          quarter of 2018, we received </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$1 billion from Biogen, comprised of $</font>625<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">
          million to purchase our stock at a 25 percent cash premium and $375 million in an upfront payment. At the commencement of this collaboration, </font>we identified one performance obligation, which was to perform R&amp;D services for Biogen.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> We determined the transaction price to be $552 million, comprised of $375 million from the upfront payment and $177 million for the premium paid by Biogen for its purchase of
          our common stock.</font> We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of marketability discount. We included a lack of marketability discount in our valuation of the premium
        because Biogen <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">received restricted shares</font>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Novartis Premiums</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">During the first quarter of 2017, we valued the premiums under the SPA agreement with Novartis. These premiums included
        the premium Novartis paid us related to its $100 million purchase of our stock in the first quarter of 2017 and the premium we could have received related to Novartis&#8217; potential purchase of our stock. These valuations required us to use level 3
        inputs, which we consider to be a critical accounting policy for our results for 2017.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We determined the fair value of the premium
          we received and the future premium we could have received by using the stated premium in the SPA and applying a </font>lack of marketability discount. We included a lack of marketability discount in our valuation of the premiums because Novartis
        received unregistered shares as part of Novartis&#8217; $100 million equity purchase and we would have issued unregistered shares to Novartis if it had purchased our common stock. Additionally, for the future potential stock purchase, we <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">estimated the probability of an Akcea IPO. At the inception of the agreements, we calculated the following fair values:</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zfe9aa208d85d48d2a0b40f966ab191e2" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$28.4 million for the premium paid by Novartis for its purchase of our common stock in the first quarter of 2017; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="ze8c5b09adb294fbb98b38106b331f4bb" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$5.0 million for the potential premium Novartis would have paid if it had purchased our common stock in the future at a premium.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Because Akcea completed its IPO before April 2018, Novartis will not purchase additional shares of Ionis stock. Therefore,
        this asset no longer had any value and we wrote-off the remaining potential premium Novartis would have paid to us if an Akcea IPO did not occur. We wrote off the amount to other expenses on our consolidated statement of operations during the third
        quarter of 2017. </font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -36pt; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Valuation of Investments in Marketable Securities</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents.
        Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term investments as &#8220;available-for-sale&#8221; and carry them at fair market value based upon prices for identical or similar
        items on the last day of the fiscal period. We record unrealized gains and losses as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments. We use the specific identification
        method to determine the cost of securities sold.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 35.3pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements.&#160;These tiers
        include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity
        securities in publicly held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified
        as available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify the majority of our securities as Level 2. We obtain the fair
        value of our Level 2 investments from our custodian bank or from a professional pricing service.&#160;We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service
        provider and comparing that fair value to the fair value based on observable market prices.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Estimated Liability for Clinical Development Costs</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We record accrued liabilities related to expenses for which service providers have not yet billed us. These liabilities
        are for products or services that we have received, specifically related to ongoing preclinical studies and clinical trials. These costs primarily relate to third-party clinical management costs, laboratory and analysis costs, toxicology studies
        and investigator grants. We have numerous medicines in concurrent preclinical studies and clinical trials at several clinical sites throughout the world. In order to ensure that we have adequately provided for ongoing preclinical and clinical
        development costs during the period in which we incur such costs, we maintain an accrual to cover these costs. We update our estimate for this accrual on at least a quarterly basis. The assessment of these costs is a subjective process that
        requires judgment. Upon settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">60</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Income Taxes</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets
        and liabilities for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and
        research and development credit carryforwards. Valuation allowances are provided when necessary to reduce deferred tax assets to the amount expected to be realized.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial
        recognition and measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by
        determining if the weight of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate
        and measure the tax benefit as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for
        income taxes. Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust
        these reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact
        the provision for income taxes in the period in which such determination is made.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax
        assets. In assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future
        taxable income. Estimates of future taxable income are based on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should
        actual amounts differ from our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> We record a valuation allowance to
          reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be realized.&#160;</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For U.S. federal income tax purposes we are required to file separate U.S. federal income tax returns for Ionis and Akcea.
        We began deconsolidating Akcea for U.S. federal income tax purposes upon Akcea&#8217;s initial public offering. As a result, we are required to assess Ionis&#8217; stand-alone and Akcea&#8217;s valuation allowances separately even though we consolidate Akcea&#8217;s
        financial results in our consolidated financial statements. We continue to file combined state tax returns in most jurisdictions. As a result, we continue to assess the state portion of our valuation allowance for those jurisdictions on a
        consolidated basis.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have historically recorded a valuation allowance against all our net deferred tax assets due to cumulative financial
        statement losses. However, in the fourth quarter of 2018, we reversed the valuation allowance previously recorded against Ionis&#8217; stand-alone U.S. federal net deferred tax assets, resulting in a one-time non-cash tax benefit of $332.1 million. Given
        our current stand-alone Ionis pre-tax income, and assuming we maintain this current level of Ionis stand-alone pre-tax income, we expect to generate income before taxes in the U.S. in future periods at a level that would result in us fully
        utilizing our U.S. federal net operating loss carryforwards and most of our existing Research and Development and Orphan Drug tax credit carryforwards over the next three years.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We continue to maintain a full valuation allowance of $234.2 million against all of Akcea&#8217;s net deferred tax assets and
        the net state deferred tax assets of Ionis at December 31, 2018 due to uncertainties related to our ability to realize the tax benefits associated with these assets.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate
        due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings.
        Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment.
        Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our
        foreign subsidiaries.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:22c7bf19-845d-4205-97fb-59be8e1cbc35">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Results of Operations</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whenever we refer to prior period results, they reflect the impact of Topic 606, which we adopted in the first quarter of
        2018.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Years Ended December 31, 2018 and December 31, 2017</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">61</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Revenue</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total revenue for 2018 was $599.7 million, compared to $514.2 million in 2017 and was comprised of the following (amounts
        in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z7e12bad4be4f41338353ffc0b3bddcf3" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">237,930</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -27pt; margin-left: 45pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI product sales, net</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,237</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 45pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total commercial revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Amortization from upfront payments</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">97,646</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Milestone payments</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">82,771</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">152,008</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">License fees</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">102,053</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">116,095</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other services</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">35,233</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,416</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 45pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total R&amp;D revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">344,752</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">394,165</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 81pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">599,674</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">514,179</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The increase in revenue in 2018 compared to 2017 was primarily due to increasing commercial revenue from SPINRAZA
        royalties, which more than doubled. We added TEGSEDI product sales in the fourth quarter of 2018. Additionally, we more than doubled our licensing and royalty revenue in 2018 compared to 2017, primarily from<font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;"> the license fee we earned from PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin America</font>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue from the amortization of upfront payments increased over $25 million in 2018 compared to 2017. The
        increase in amortization was primarily due to our 2018 strategic neurology collaboration with Biogen. Additionally, we added amortization revenue from our new collaboration with Roche to develop IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>in 2018. Our R&amp;D revenue
        from milestone payments, license fees and other services continued to make a significant contribution to our financial results.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Already in the first quarter of 2019, we have earned $185 million. We earned $150 million from Novartis when it licensed
        AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and $35 million from Roche when it dosed the first patient in the Phase 3 study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in patients with Huntington&#8217;s disease.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Operating Expenses</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Operating expenses for 2018 were $661.0
          million, and increased compared to $483.1 million for 2017. Our operating expenses increased year over year principally due to higher SG&amp;A expenses as we prepared to commercialize TEGSEDI and WAYLIVRA. Our SG&amp;A expenses also increased
          year over year because of fees we owed under our in-licensing agreements related to SPINRAZA. </font>We earn tiered royalties on annual SPINRAZA sales and pay nominal fixed third-party royalties that are not tiered.<font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;"> R&amp;D expenses accounted for a smaller portion of the increase in operating expenses. R&amp;D expenses for 2018 increased compared to 2017 primarily due to increases in drug development costs
          related to several medicines, including AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, as we, with Akcea, advanced these programs in development. </font>These increases reflect
        the investment we are making in advancing and expanding our pipeline.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our operating expenses by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z3c8efc5c8ff84b4eadb6bbea238b19bf" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">293,175</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">305,352</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">251,408</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">146,332</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(14,849</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(54,527</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">529,734</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">397,157</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">131,312</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">85,975</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total operating expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">661,046</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">483,132</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In order to analyze and compare our results of operations to other similar companies, we believe it is important to
        exclude non-cash compensation expense related to equity awards from our operating expenses. We believe non-cash compensation expense is not indicative of our operating results or cash flows from our operations. Further, we internally evaluate the
        performance of our operations excluding it.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">62</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Cost of Products Sold</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our cost of products sold consisted of manufacturing costs, including certain fixed costs, transportation and freight,
        indirect overhead costs associated with the manufacturing and distribution of TEGSEDI, certain associated period costs. We not expect our fixed costs will increase in direct correlation to TEGSEDI product sales. We expensed a significant portion of
        the cost of producing TEGSEDI that Akcea is using in the commercial launch as R&amp;D expense prior to the regulatory approval of TEGSEDI. We expect cost of products sold to increase as we deplete these inventories.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our cost of products sold by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z351e947cc62844df885026a5bc1825ca" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,573</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(9,913</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,660</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">160</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total cost of products sold</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,820</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For 2018, our cost of products sold was $1.7 million. We began recognizing cost of products sold in 2018 when TEGSEDI
          was approved. We previously recognized $0.1 million of costs to produce TEGSEDI related to the TEGSEDI commercial revenue we recognized in 2018 because we incurred these costs before we obtained regulatory approval. We did not have cost of
          products sold in 2017. Akcea includes the amortization for milestone payments it made to us related to the U.S. and European approvals of TEGSEDI in its cost of products sold. Akcea is recognizing this amortization over TEGSEDI&#8217;s remaining
          estimated patent life. This amortization is eliminated in our consolidated results. All amounts exclude non-cash compensation expense related to equity awards.</font></div>
    </div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Research, Development and Patent Expenses</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our research, development and patent expenses consist of expenses for antisense drug discovery, antisense drug
        development, manufacturing and operations and R&amp;D support expenses.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth information on research, development and patent expenses (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z446cd3123fc744d7a90d239fd1b3670d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research, development and patent expenses, excluding non-cash compensation expense related to
                equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">338,047</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">310,123</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">76,557</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">64,521</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total research, development and patent expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">414,604</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">374,644</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For 2018, our research, development and patent expenses were $338.0 million, compared to $310.1 million for 2017. The
          increase in our R&amp;D expenses for 2018, compared to 2017 was driven primarily by increases in drug development costs related to several medicines including AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>and AKCEA-ANGPTL3-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, as we advanced these
          programs in development. All amounts exclude non-cash compensation expense related to equity awards.</font></div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our research, development and patent expenses by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="ze88ad134c48a42538d310a5d6f4a6c8c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">222,528</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">246,390</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120,905</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">118,260</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,386</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(54,527</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">338,047</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">310,123</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">76,557</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">64,521</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total research, development and patent expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">414,604</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">374,644</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Antisense Drug Discovery</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use our proprietary antisense technology to generate information about the function of genes and to determine the value
        of genes as drug discovery targets. We use this information to direct our own antisense drug discovery research, and that of our partners. Antisense drug discovery is also the function that is responsible for advancing our antisense core
        technology.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">63</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As we continue to advance our antisense technology, we are investing in our drug discovery programs to expand our and our
        partners&#8217; drug pipelines. Our antisense drug discovery expenses are part of our Ionis Core business segment.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our antisense drug discovery expenses were as follows (in thousands) and are part of our Ionis Core business segment:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z2154d0c77aab4c4bbd91273694a279d0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense drug discovery expenses, excluding non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">61,387</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">56,160</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">17,530</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15,203</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total antisense drug discovery expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">78,917</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">71,363</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense drug discovery expenses for 2018 were $61.4 million and were slightly higher compared to $56.2 million for 2017
        due to an increase in expenses we incurred in 2018 related to our expanding early stage research programs. All amounts exclude non-cash compensation expense related to equity awards.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Antisense Drug Development</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth drug development expenses, including the breakdown for medicines in Phase 3 development
        and/or commercialization for which we have incurred significant costs (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z80c0f4f1ed3242ae87d29931897ef42b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,996</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">WAYLIVRA</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">19,397</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,524</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">19,204</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24,880</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other antisense development projects</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">116,936</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">79,106</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Development overhead expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48,754</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,784</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total antisense drug development, excluding non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">204,291</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">181,290</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">34,845</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,325</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total antisense drug development expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">239,136</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">209,615</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense drug development expenses were
          $204.3 million for 2018 and increased compared to $181.3 million for 2017. During 2018, our development expenses for AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and
          AKCEA-ANGPTL3-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> increased compared to 2017. We completed enrollment of the Phase 2 clinical study of AKCEA-APO(a)-</font>L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> during the first quarter of 2018 and reported positive Phase 2 data in the third quarter of 2018. We also initiated a Phase 2 clinical study of AKCEA-APOCIII-</font>L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in patients with hypertriglyceridemia and established cardiovascular disease in the first quarter of 2018. Slightly offsetting these increases were decreased expenses for
          SPINRAZA, TEGSEDI and WAYLIVRA. Specifically, we have transitioned all further development of SPINRAZA to Biogen. In early 2017, we completed our Phase 3 WAYLIVRA trial in patients with FCS and our Phase 3 TEGSEDI trial in patients with hATTR
          with polyneuropathy. All amounts exclude non-cash compensation expense related to equity awards.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our antisense drug development expenses by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z77509dbd5f1f415491723c57fbcbed3a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">100,090</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">123,934</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">104,201</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">105,751</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(48,395</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">204,291</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">181,290</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">34,845</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,325</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total antisense drug development expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">239,136</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">209,615</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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 products 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 product. Although we may characterize a product 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 products based on each product&#8217;s particular needs at that time. This means we are constantly shifting resources among products. Therefore, what we spend on each product during a particular period is usually a function of what is
        required to keep the products progressing in clinical development, not what products 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 product to another and cannot be used to accurately predict future costs for each product. And,
        because we always have numerous medicines in preclinical and early stage clinical research, the fluctuations in expenses from drug to drug, in large part, offset one another. If we partner a drug, it may affect the size of a trial, its timing, its
        total cost and the timing of the related costs.</font></div>
    <div style="text-align: left;"><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">64</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Manufacturing and Operations</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expenditures in our manufacturing and operations function consist primarily of personnel costs, specialized chemicals for
        oligonucleotide manufacturing, laboratory supplies and outside services. Our manufacturing and operations function is responsible for providing drug supplies to antisense drug development, Akcea and our collaboration partners. Our manufacturing
        procedures include testing to satisfy good laboratory and good manufacturing practice requirements.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our manufacturing and operations expenses were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z19030715c4b2408b809e4044ad14d3fc" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Manufacturing and operations expenses, excluding non-cash compensation expense related to equity
                awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">39,806</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,526</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,036</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,904</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total manufacturing and operations expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48,842</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50,430</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Manufacturing and operations expenses were $39.8 million for 2018 and declined slightly compared to $43.5 million for
        2017. All amounts exclude non-cash compensation expense related to equity awards.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our manufacturing and operations expenses by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zcbca06fe93a7418ea551af6cedd905d7" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">32,277</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">39,098</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,758</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,440</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,229</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(6,012</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">39,806</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,526</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,036</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,904</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total manufacturing and operations expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48,842</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50,430</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

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    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>R&amp;D Support</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In our research, development and patent expenses, we include support costs such as rent, repair and maintenance for
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    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth information on R&amp;D support expenses (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zfa7365c9b76e4c00baca82d52702ba65" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Personnel costs</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,968</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,432</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Occupancy</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,567</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,236</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Patent expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,744</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,095</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Depreciation and amortization</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">439</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">249</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Insurance</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,622</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,735</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,223</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total R&amp;D support expenses, excluding non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">32,563</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">29,147</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15,146</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,089</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total R&amp;D support expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">47,709</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,236</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D support expenses for 2018 were $32.6 million compared to $29.1 million for 2017. R&amp;D support expenses
        increased slightly primarily related to costs associated with the expansion of our business. All amounts exclude non-cash compensation expense related to equity awards.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">65</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our R&amp;D support expenses by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zd07bac003df747ad9461e7cbef946634" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,774</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">27,198</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,946</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,069</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(157</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(120</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">32,563</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">29,147</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15,146</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,089</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total R&amp;D support expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">47,709</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,236</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Selling, General and Administrative Expenses</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selling, general and administrative expenses include costs associated with the pre-commercialization and commercialization
        activities for our medicines and costs to support our company, our employees and our stockholders. These costs include personnel and outside costs in the areas of pre-commercialization, commercialization, 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth information on selling, general and administrative expenses (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zc723742cff0d416abc47f02924de9ad5" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selling, general and administrative expenses, excluding non-cash compensation expense related to
                equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">190,027</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">87,034</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">54,595</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,454</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total selling, general and administrative expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">244,622</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,488</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selling, general and administrative expenses
          were $190.0 million for 2018 and significantly increased compared to $87.0 million for 2017. </font>The increase in SG&amp;A expenses was principally due to the cost of preparing<font style="font-size: 10pt; font-family: 'Times New Roman',
          Times, serif;">&#160;</font>to commercialize <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI and WAYLIVRA</font>, and an increase in the fees we owed under our in-licensing<font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">&#160;</font>agreements related to SPINRAZA. We project our expenses will increase as we continue to launch TEGSEDI.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> All
          amounts exclude non-cash compensation expense related to equity awards.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our selling, general and administrative expenses by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zd66589926b3549cc90b168fe8fb24681" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">70,647</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">58,962</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">118,930</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,072</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">450</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">190,027</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">87,034</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">54,595</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,454</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total selling general and administrative expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">244,622</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,488</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Akcea Therapeutics, Inc.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth information on&#160;operating expenses (in thousands) for our Akcea Therapeutics business
        segment:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zd7b9dded20174e5699a9929d5c5e8f8d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cost of products sold</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,573</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Development and patent expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">118,260</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selling, general and administrative expenses</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">118,930</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,072</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">251,408</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">146,332</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">44,275</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">17,539</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total Akcea Therapeutics operating expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">295,683</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">163,871</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Operating expenses for Akcea were $251.4 million for 2018 and increased compared to $146.3 million for 2017.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">66</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the third quarter of 2018, Akcea began recognizing cost of products sold expenses after the approval of TEGSEDI.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In 2017, $48.4 million of development and patent expenses was for one-time sublicensing expenses related to the Novartis
        collaboration recorded in the first quarter of 2017. $33.4 million of these expenses were non-cash and the remaining $15 million was paid to us. Excluding the $48.4 million of one-time expenses, Akcea&#8217;s development and patent expenses increased
        $51.0 million in 2018 compared to 2017 as Akcea made investments in advancing its pipeline, including AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, and AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. For each period presented, we allocated a portion of Ionis&#8217; R&amp;D support
        expenses, which are included in development and patent expenses in the table above, to Akcea for work we performed on behalf of Akcea.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s SG&amp;A expenses increased in 2018 compared to 2017, primarily because Akcea was building its commercial
        infrastructure and advancing the pre-commercialization activities necessary to successfully launch TEGSEDI and WAYLIVRA. For each period presented, we allocated a portion of Ionis&#8217; G&amp;A expenses, which were included in Akcea&#8217;s G&amp;A expenses
        in the table above, to Akcea for work we performed on Akcea&#8217;s behalf.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Investment Income</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Investment income for 2018 was $30.2 million compared to $8.2 million for 2017. Investment income increased primarily due
        to a significantly higher average cash balance and to a lesser extent an improvement in the market conditions during 2018 compared to 2017.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Interest Expense</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Interest expense was $44.8 million for both 2018 and 2017. The following table sets forth information on interest expense
        (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z83f8de6ea7f743308275705a92befec2" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Convertible notes:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash amortization of the debt discount and debt issuance&#160;costs</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">35,173</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">32,536</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Interest expense payable in cash</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,855</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,090</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash interest expense for long-term financing liability</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,352</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Interest on mortgage for primary R&amp;D and manufacturing facilities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,409</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,103</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">352</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">671</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">44,789</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">44,752</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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    </table>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In July 2017, </font>we purchased the
        building that houses our primary R&amp;D facility and the building that houses our manufacturing facility for $79.4 million and $14.0 million, respectively. As a result of the purchase of our primary R&amp;D facility, we <font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">extinguished the financing liability we had previously recorded on our balance sheet. </font>We financed the purchase of the buildings with mortgage debt of $51.3 million with an interest rate
        of 3.88 percent for our primary R&amp;D facility and mortgage debt of $9.1 million with an interest rate of 4.2 percent for our manufacturing facility. Both mortgages mature in August 2027.</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Loss on Extinguishment of Financing Liability for Leased Facility</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognized a loss on extinguishment of the financing liability for leased facility of $7.7 million in 2017. The loss
        represents the difference between the amount we previously recorded as a financing liability for the leased facility and the purchase price we paid for our primary R&amp;D facility in July 2017. This loss was non-cash and nonrecurring.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Other Expenses</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other expenses were $0.2 million in 2018 and $3.5 million for 2017. Our 2017 other expenses primarily consisted of the
        previously capitalized fair value of the potential premium we would have received from Novartis if Akcea had not completed its IPO. This expense was non-cash and nonrecurring.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Income Tax Benefit</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We had an income tax benefit of $291.1
          million for 2018, compared to $6.0 million for 2017</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. </font>Our tax benefit increased significantly in 2018 primarily due to a one-time, non-cash tax benefit
        related to the reversal of the valuation allowance previously recorded against Ionis&#8217; stand-alone U.S. federal net deferred tax assets of <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$332.1 million</font>. Because
        of Ionis&#8217; strong financial performance, on a stand-alone basis, over the past few years and our outlook regarding the continued growth of our business, we determined<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> that
          it is more likely than not that we will utilize most of our deferred federal income tax assets primarily </font>net operating loss carryforwards and research and development and orphan drug credit carryforwards. <font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">We continue to maintain a valuation allowance against certain Ionis and Akcea federal and state net deferred tax assets at December 31, 2018 due to uncertainties related to our ability to realize the
          tax benefits associated with these assets.</font></font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">67</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Net Income (Loss)</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We had income of $215.0 million for 2018, compared to a net loss of $10.8 million for 2017. The increase in our net income
        in 2018, compared to 2017 was primarily due to our increasing revenues and income tax benefit.</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Net Operating Loss and Tax Credit Carryforwards</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At December 31, 2018, we had federal and California tax net operating loss carryforwards of $284.6 million and $808.7
        million, respectively. Our federal tax loss carryforwards begin to expire in 2033. A portion of our California tax loss carryforwards continued to expire in 2018. At December 31, 2018, we also had federal and California research and development tax
        credit carryforwards of $288.9 million and $68.4 million, respectively.&#160;Our Federal research and development tax credit carryforwards began to expire in 2018. Our California research and development tax credit carryforwards are available
        indefinitely.</font></div>
    <div><br>
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    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At December 31, 2018, we owned approximately 75 percent of Akcea. The shares of Akcea third parties own represent an
        interest in Akcea's equity that we do not control. However, because we continue to maintain overall control of Akcea through our voting interest, we reflect the assets, liabilities and results of operations of Akcea in our consolidated financial
        statements. We reflect the noncontrolling interest attributable to other owners of Akcea's common stock in a separate line called &#8220;Net loss attributable to noncontrolling interest in Akcea&#8221; on our statement of operations. Our noncontrolling
        interest in Akcea on our statement of operations for 2018 was $58.8 million, compared to $11.1 million for 2017.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></font></div>
    <div><br>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Net Income Attributable to Ionis Pharmaceuticals, Inc. Common Stockholders<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and Net Income per Share</font></font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We had net income attributable to our common stockholders of $273.7 million for 2018, compared $0.3 million in 2017. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic and diluted net income per share for 2018 was $2.09 and $2.07, respectively compared to $0.15 for 2017. The increase in our net income attributable to</font> our common
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    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:4c35d8af-135f-4941-80ae-f0864d93a77f">
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    <div><br>
    </div>
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        $514.2 million compared to $372.8 million for 2016 and was comprised of the following (amounts in thousands):</font></div>
    <div><br>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112,540</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -27pt; margin-left: 45pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Licensing and other royalty revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,474</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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: 45pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total commercial revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120,014</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,767</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
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          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Amortization from upfront payments</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">97,646</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">62,415</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">152,325</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">License fees</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">116,095</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">98,000</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other services</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,416</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">37,269</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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        <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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total R&amp;D revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">394,165</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">350,009</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 81pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">514,179</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">372,776</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The increase in revenue in 2017 compared to 2016 was primarily due to increasing commercial revenue from SPINRAZA
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    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our revenue from licensing and other royalties was higher in 2016 primarily from $15 million we earned from Kastle when it
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    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue from the amortization of upfront payments increased $35 million in 2017, compared to 2016, primarily due
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    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In 2017, R&amp;D revenue from milestone payments included&#160;over $120 million&#160;of milestone payments from Biogen, including
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    <div><br>
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    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">68</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    <div><br>
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      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
      </div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our operating expenses by segment were as follows (in thousands):</font></div>
    <div><br>
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    <table cellspacing="0" cellpadding="0" id="zf4427127db5f4c459b97b5bd8cf48ce1" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">305,352</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">260,233</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">146,332</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">73,363</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: rgb(204, 238, 255);">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: rgb(204, 238, 255);">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: rgb(204, 238, 255); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: rgb(204, 238, 255); border-bottom: 2px solid rgb(0, 0, 0);">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(54,527</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: rgb(204, 238, 255);">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: rgb(204, 238, 255);">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
          <td valign="bottom" 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><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,768</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: rgb(204, 238, 255);">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">397,157</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">320,828</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">85,975</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,108</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total operating expenses</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">483,132</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">392,936</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Research, Development and Patent Expenses</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth information on research, development and patent expenses (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zf73891736576484b8941eb4386d1c1ab" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research, development and patent expenses, excluding non-cash compensation expense related to
                equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">310,123</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">289,221</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">64,521</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">55,099</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total research, development and patent expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">374,644</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">344,320</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For 2017, total research, development and patent expenses were $310.1 million, compared to $289.2 million for 2016. Our
        research, development and patent expenses increased slightly primarily related to expenses such as regulatory filings, manufacturing initial launch supplies and other activities in support of TEGSEDI and WAYLIVRA. If you exclude these expenses, our
        research, development and patent expenses decreased year-over-year. All amounts exclude non-cash compensation expense related to equity awards.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our research, development and patent expenses by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z45b56eef9a7c4ae5a6d5a2589a93eb49" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">246,390</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">238,106</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">118,260</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">63,883</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(54,527</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,768</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">310,123</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">289,221</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">64,521</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">55,099</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total research, development and patent expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">374,644</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">344,320</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Antisense Drug Discovery</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our antisense drug discovery expenses were as follows (in thousands) and are part of our Ionis Core business segment:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z74dc4f21f7b7412085180eca6ac77d31" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense drug discovery expenses, excluding non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">56,160</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">51,028</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15,203</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13,589</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total antisense drug discovery expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">71,363</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">64,617</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense drug discovery expenses for 2017 were $56.2 million and were slightly higher compared to $51.0 million for 2016,
        due to expenses we incurred related to advancing our early stage research programs. All amounts exclude non-cash compensation expense related to equity awards.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">69</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Antisense Drug Development</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth research and development expenses for our major antisense drug development projects (in
        thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zceb2d74b651b4985a1095e1f75a1d042" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,996</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,868</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">WAYLIVRA</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,524</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,285</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24,880</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,939</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other antisense development products</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">79,106</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">42,999</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Development overhead expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,784</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">42,966</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total antisense drug development, excluding non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">181,290</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">179,057</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,325</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,380</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total antisense drug development expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">209,615</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">200,437</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Antisense drug development expenditures were $181.3 million for 2017 compared to $179.1 million for 2016. The expenses for
        SPINRAZA and WAYLIVRA declined in 2017. Specifically, we transitioned all further development of SPINRAZA to Biogen and we were completing our Phase 3 WAYLIVRA trial in patients with FCS. Additionally, we completed our Phase 3 TEGSEDI trial in
        patients with hATTR with polyneuropathy in 2017. Our 2017 expenses included $4.8 million of expenses related to regulatory filing activities for TEGSEDI and WAYLIVRA. Additionally, during 2017, we made investments in our other antisense development
        projects, including AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. All amounts exclude non-cash compensation expense related to equity awards.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our antisense drug development expenses by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z794677295afa4e8a9d0a8c6f8773afc9" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">123,934</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">132,418</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">105,751</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">46,639</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(48,395</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">181,290</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">179,057</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,325</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,380</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total antisense drug development expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">209,615</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">200,437</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Manufacturing and Operations</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our manufacturing and operations expenses were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zf3d35cb2ef9e4460928d53d7bcf56843" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Manufacturing and operations expenses, excluding non-cash compensation expense related to equity
                awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,526</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,148</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,904</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,113</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total manufacturing and operations expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50,430</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">36,261</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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    </table>
    <div><br>
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        $43.5 million and were higher compared to $30.1 million for 2016. All amounts exclude non-cash compensation expense related to equity awards. $11 million of the increase in manufacturing expenses was related to TEGSEDI and WAYLIVRA to prepare for
        the planned launches. All amounts exclude non-cash compensation expense related to equity awards.</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our manufacturing and operations expenses by segment were as follows (in thousands):</font></div>
    <div><br>
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    <table cellspacing="0" cellpadding="0" id="zf1a3c9d9c179416d903a0b9ffc99923c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">39,098</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">27,341</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,440</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15,455</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(6,012</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,648</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,526</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,148</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,904</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,113</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total manufacturing and operations expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50,430</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">36,261</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">70</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>R&amp;D Support</u></font></font></div>
    <div><br>
    </div>
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    <div><br>
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    <table cellspacing="0" cellpadding="0" id="z861c8b52e0d5406799a3171f4db6b20c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Personnel costs</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,432</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,560</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Occupancy</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,236</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,891</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Patent expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,095</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,945</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Depreciation and amortization</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">249</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">245</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Insurance</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,735</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,344</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,003</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total R&amp;D support expenses, excluding non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">29,147</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,988</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,089</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,017</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total R&amp;D support expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,236</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,005</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D support expenses for 2017 were $29.1 million, and were essentially flat compared to $29.0 million for 2016. All
        amounts exclude non-cash compensation expense related to equity awards.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our R&amp;D support expenses by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zfde9fb1d03da4763b0636b7e0b32b008" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">27,198</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">27,319</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,069</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,789</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elimination of intercompany activity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(120</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(120</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">29,147</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,988</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,089</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total R&amp;D support expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,236</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,005</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Selling, General and Administrative Expenses</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth information on selling, general and administrative expenses (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z52b4eb6bb49c484b9a78b71d08df755b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selling, general and administrative expenses, excluding non-cash compensation expense related to
                equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">87,034</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">31,607</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,454</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">17,009</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total selling, general and administrative expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,488</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48,616</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selling, general and administrative expenses
        </font>for 2017 were $87.0 million and increased compared to $31.6 million for 2016. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The increase in SG&amp;A expenses was principally due to the cost of preparing to
          commercialize TEGSEDI and WAYLIVRA and from fees we owed under our in-licensing agreements related to SPINRAZA. All amounts exclude non-cash compensation expense related to equity awards.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our selling, general and administrative expenses by segment were as follows (in thousands):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z8661f2459e8b40d797056bfd4b158f03" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Core</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">58,962</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,127</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,072</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,480</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,454</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">17,009</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total selling, general and administrative expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,488</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48,616</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">71</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Akcea Therapeutics, Inc.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth information on&#160;operating expenses (in thousands) for our Akcea Therapeutics business
        segment:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zdf6b5ab48bc74047b33930a531705e90" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Development and patent expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">118,260</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">63,883</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">General and administrative expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,072</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,480</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">146,332</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">73,363</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash compensation expense related to equity awards</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">17,539</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,149</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total Akcea Therapeutics operating expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">83,512</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s operating expenses were $146.3 million for 2017 and increased compared to $73.4 million for 2016.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$48.4 million of the increase in Akcea&#8217;s development and patent expenses was for one-time sublicensing expenses related to
        the Novartis collaboration recorded in the first quarter of 2017. $33.4 million of these expenses were non-cash and the remaining $15 million was paid to us. For each period presented, we allocated a portion of Ionis&#8217; R&amp;D support expenses,
        which are included in development and patent expenses in the table above, to Akcea for work we performed on behalf of Akcea.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s G&amp;A expenses increased in 2017, compared to 2016, primarily due to Akcea continuing to build its commercial
        infrastructure and advance the pre-commercialization activities necessary to successfully launch WAYLIVRA. For each period presented, we allocated a portion of Ionis&#8217; G&amp;A expenses, which were included in Akcea&#8217;s G&amp;A expenses in the table
        above, to Akcea for work we performed on Akcea&#8217;s behalf.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">All amounts exclude non-cash compensation expense related to equity awards.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Investment Income</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Investment income for 2017 totaled $8.2 million compared to $5.5 million for 2016.&#160;Investment income increased primarily
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    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Interest Expense</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth information on interest expense (in thousands):</font></div>
    <div><br>
    </div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Convertible notes:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash amortization of the debt discount and debt issuance&#160;costs</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">32,536</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">25,115</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Interest expense payable in cash</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,090</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,684</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-cash interest expense for long-term financing liability</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,352</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,693</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Interest on mortgage for primary R&amp;D and manufacturing facilities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,103</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">671</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">303</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total interest expense</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">44,752</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">38,795</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Loss on Extinguishment of Financing Liability for Leased Facility</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognized a loss on extinguishment of the financing liability for leased facility of $7.7 million in 2017. The loss
        represents the difference between the amount we previously recorded as a financing liability for the leased facility and the purchase price we paid for our primary R&amp;D facility in July 2017. This loss was non-cash and nonrecurring.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Early Retirement of Debt</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As a result of the debt exchange we completed in December 2016, we recorded a $4.0 million non-cash loss on early
        retirement of debt, reflecting the early retirement of the majority of our remaining 2&#190;&#160;percent convertible notes in December 2016.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Other Expenses</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other expenses were $3.5 million for 2017 and primarily consisted of the previously capitalized fair value of the
        potential premium we would have received from Novartis if Akcea had not completed its IPO. This expense was non-cash and nonrecurring.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">72</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Income Tax Expense (Benefit)</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In 2017, we recorded a net income tax benefit of $6.0 million, compared to income tax expense of $2.9 million in 2016. Our
        tax expense flipped from an expense position in 2016 to a benefit position in 2017 primarily due to a $7.7 million reduction in our valuation allowance. As a result of the Tax Act, we reduced our valuation allowance because we are entitled to
        receive a tax refund for our cumulative prior year alternative minimum tax credit carryforwards.</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Net Loss</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net loss for 2017 was $10.8 million compared $60.4 million for 2016. <font style="font-size: 10pt; font-family: 'Times
          New Roman', Times, serif;">Our net loss improved for 2017&#160;compared to 2016 primarily due to the addition of commercial revenue from SPINRAZA royalties and increased R&amp;D revenue.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Net Loss Attributable to Noncontrolling Interest in Akcea Therapeutics, Inc.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As a result of Akcea&#8217;s IPO, beginning in July 2017, we no longer own 100 percent of Akcea. From the closing of Akcea&#8217;s IPO
        on July 19, 2017 through the end of 2017, we owned approximately 68 percent of Akcea. As a result, we adjusted our financial statements to reflect the portion of Akcea we no longer own, which was 32 percent at December 31, 2017. Accordingly, our
        consolidated statement of operations now includes a new line called &#8220;Net loss attributable to noncontrolling interests in Akcea&#8221;; our noncontrolling interest in Akcea for 2017 was $11.1 million.&#160;We also added a corresponding account to our
        consolidated balance sheet called &#8220;Noncontrolling interest in Akcea Therapeutics, Inc.&#8221;</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Net Income (Loss) Attributable to Ionis Pharmaceuticals, Inc. Common Stockholders<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and Net Income (Loss) per Share</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We had net income attributable to our common stockholders of $0.3 million for 2017, compared to a net loss of $60.4
        million in 2016. Basic and diluted net income per share for 2017 was $0.15 compared to basic and dilutive net loss per share of $0.50 for 2016.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:e76bd30e-462d-4c34-a8fc-3ef3d97f96f4">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Liquidity and Capital Resources</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have financed our operations primarily
          from research and development collaborative agreements. Beginning in December 2016 we added commercial revenue from SPINRAZA royalties. From our inception through December 31, </font>2018, we had earned approximately $3.2 billion<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in revenue.&#160;We also financed our operations through the sale of our equity securities and the issuance of long-term debt. From the time we were founded through December 31, </font>2018<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, we had raised net proceeds of approximately $1.7</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">billion from the sale of our equity
          securities, not including the $182.4 million Akcea received in net proceeds from its IPO in July 2017. Additionally, we borrowed approximately $1.4 billion under long-term debt arrangements to finance a portion of our operations over the same
          time period.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At December 31, 2018, we had cash, cash equivalents and short-term investments of $2.1 billion and stockholders&#8217; equity of
        $1,187.2 million. In comparison, we had cash, cash equivalents and short-term investments of $1.0 billion and stockholders&#8217; equity of $365.3 million at December&#160;31, 2017.&#160;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our





          cash, cash equivalents and short-term investments increased in 2018 primarily from the $1 billion payment we received from Biogen for our 2018 strategic neurology collaboration.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At December 31, 2018, we had consolidated working capital of $1.9 billion compared to $925.1 million at December 31, 2017.
        <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As of December 31, 2018, our debt and other obligations totaled $764.0 million compared to $759.8 million at December 31, 2017.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table summarizes our contractual obligations as of December 31, 2018. 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:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z2f7b7c11c9b641569c4db703822e6473" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="18" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Payments Due by Period (in millions)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Contractual Obligations</font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(selected&#160;balances&#160;described&#160;below)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Total</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Less than</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">1 year</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">1-3 years</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">3-5 years</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">After</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">5 years</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Convertible senior notes (principal and interest payable)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">706.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">699.2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Building mortgage payments</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">80.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6.2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">67.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Financing arrangements (principal and interest payable)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other obligations (principal and interest payable)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Operating leases</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">25.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 40%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">826.2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">25.2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">709.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">79.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our contractual obligations consist primarily of our convertible debt. In addition, we also have facility mortgages,
        facility leases, equipment financing arrangements and other obligations. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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 $68.3 million of gross unrecognized tax benefits from our
          contractual obligations table above.</font></font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">73</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">1 Percent Convertible Senior Notes</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In November 2014, we completed a $500 million
          offering of convertible senior notes, which mature in 2021 and bear interest at 1 percent. </font>We used a substantial portion of the net proceeds from the issuance of the 1 percent convertible senior notes to repurchase $140 million in
        principal of our 2&#190; percent convertible senior notes. As a result, the principal balance of the 2&#190; percent notes following the repurchase in November 2014 was $61.2 million.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2016, we issued an additional $185.5 million of 1 percent convertible senior notes in exchange for the
        redemption of $61.1 million of our 2&#190; percent convertible senior notes. At December 31, 2018, we had a nominal amount of our 2&#190; percent convertible senior notes outstanding. At December 31, 2018, we had the following 1 percent convertible senior
        notes outstanding (amounts in millions except price per share data):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z4b842cfb2e9a4128ba00299f02479562" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">1 Percent Convertible</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Senior Notes</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Outstanding principal balance</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">685.5</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Original issue date ($500 million of principal)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">November 2014</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additional issue date ($185.5 million of principal)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: top; background-color: #CCEEFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">December 2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Maturity date</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">November 2021</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Interest rate</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: top; background-color: #CCEEFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1 percent</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Conversion price per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">66.81</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total shares of common stock subject to conversion</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Interest is payable semi-annually for the 1 percent notes. The notes are convertible under certain conditions, at the
        option of the note holders. We 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 1 percent notes prior to maturity, and no sinking fund is provided for them.
        Holders of the 1 percent notes may require us to purchase some or all of their notes upon the occurrence of certain fundamental changes, as set forth in the indenture governing the 1 percent notes, at a purchase price equal to 100 percent of the
        principal amount of the notes to be purchased, plus accrued and unpaid interest.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Financing Arrangements</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 2015, we entered into a five-year revolving line of credit agreement with Morgan Stanley Private Bank, National
        Association, or Morgan Stanley. We amended the credit agreement in February 2016 to increase the amount available for us to borrow. Under the amended credit agreement, Morgan Stanley will provide a maximum of $30 million of revolving credit for
        general working capital purposes. Any loans under the credit agreement have interest payable monthly in arrears at a borrowing rate based on our option of:</font></div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zec521c75ad3646a8ab5c8c5e5a3f9056" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

          <tr>
            <td style="width: 58.5pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(i)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">a floating rate equal to the one-month London Interbank Offered Rate, or LIBOR, in effect plus 1.25 percent per annum;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zbda98378d76c40d9823942f291aeff96" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

          <tr>
            <td style="width: 58.5pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(ii)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">a fixed rate equal to LIBOR plus 1.25 percent for a period of one, two, three, four, six, or twelve months as elected by us; or</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z9d3f53ed0ed445eeb5a4d7a4d7e5e3ac" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

          <tr>
            <td style="width: 58.5pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(iii)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">a fixed rate equal to the LIBOR swap rate during the period of the loan.</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additionally, we pay 0.25 percent per annum, payable quarterly in arrears, for any amount unused under the credit
        facility. As of December 31, 2018 we had $12.5 million in outstanding borrowings under the credit facility with a 2.31 percent fixed interest rate and a maturity date of September 2019, which we used to fund our capital equipment needs.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The credit agreement includes customary affirmative and negative covenants and restrictions. We are in compliance with all
        covenants of the credit agreement.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Research and Development and Manufacturing Facilities</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In July 2017, </font>we purchased the
        building that houses our primary R&amp;D facility and the building that houses our manufacturing facility for $79.4 million and $14.0 million, respectively. We financed the purchase of our primary R&amp;D facility and manufacturing facility, with
        mortgage debt of $51.3 million and $9.1 million, respectively. Our primary R&amp;D facility mortgage has an interest rate of 3.88 percent. Our manufacturing facility mortgage has an interest rate of 4.20 percent. During the first five years of both
        mortgages we are only required to make interest payments. Both mortgages mature in August 2027.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Other Obligations</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In addition to contractual obligations, we had outstanding purchase orders as of December 31, 2018 for the purchase of
        services, capital equipment and materials as part of our normal course of business.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We plan to continue to enter into collaborations with partners to 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.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">74</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Off-Balance Sheet Arrangements</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have not entered into, nor do we currently have, any off-balance sheet arrangements (as defined under SEC rules).</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:c1a319ba-843c-42a7-9979-59b8d0c1535c">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 7A. Quantitative and Qualitative Disclosures About Market Risk</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are exposed to changes in interest rates primarily from our long-term debt arrangements and, secondarily, 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.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 8. Financial Statements and Supplementary Data</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We filed our consolidated financial statements and supplementary data required by this item as exhibits hereto, and listed
        them under Item 15(a)(1)&#160;and (2), and incorporate them herein by reference.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">None.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 9A. Controls and Procedures</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Disclosure Controls and Procedures</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We maintain disclosure controls and procedures (as defined in Rules&#160;13a-15(e)&#160;and&#160;15d-15(e)&#160;under the Securities Exchange
        Act of 1934, as amended, or Exchange Act) that are designed to ensure that information we are required to disclose in our Exchange Act reports is recorded, processed, summarized and reported within the time periods specified in the SEC&#8217;s rules&#160;and
        forms, and that such information is accumulated and communicated to our management, including our Chief Executive Officer and Chief Financial Officer, as appropriate, to allow timely decisions regarding required disclosure. We designed and evaluate
        our disclosure controls and procedures recognizing that any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance and not absolute assurance of achieving the desired control objectives.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As of the end of the period covered by this report on Form&#160;10-K, we carried out an evaluation of our disclosure controls
        and procedures under the supervision of, and with the participation of our management, including our Chief Executive Officer and Chief Financial Officer. Based on our evaluation, our Chief Executive Officer and Chief Financial Officer concluded
        that our disclosure controls and procedures were effective as of December 31, 2018.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Management</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s Report on Internal Control over Financial Reporting</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our management is responsible for establishing and maintaining adequate internal control over financial reporting, as
        defined in Exchange Act Rules&#160;13a-15(f). Our internal control over financial reporting is a process designed under the supervision of our Chief Executive Officer and Chief Financial Officer to provide reasonable assurance regarding the reliability
        of financial reporting and the preparation of our financial statements for external purposes in accordance with U.S. generally accepted accounting principles.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As of December 31, 2018, we assessed the effectiveness of our internal control over financial reporting based on the
        criteria for effective internal control over financial reporting under the 2013 &#8220;Internal Control&#8212;Integrated Framework,&#8221; issued by the Committee of Sponsoring Organizations, or COSO, of the Treadway Commission, under the supervision of, and with
        the participation of our management, including our Chief Executive Officer and Chief Financial Officer. Based on that assessment, our management concluded that we maintained effective internal control over financial reporting as of December 31,
        2018.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ernst&#160;&amp; Young LLP, an independent registered public accounting firm, audited the effectiveness of our internal control
        over financial reporting as of December 31, 2018, as stated in their attestation report, which is included elsewhere herein.</font></div>
    <div style="text-align: left; text-indent: 36pt;"><br>
    </div>
    <div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Changes in Internal Control over Financial Reporting</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The above assessment did not identify any change in our internal control over financial reporting that occurred during our
        latest fiscal quarter and that has materially affected, or is reasonably likely to materially affect, our internal control over financial reporting.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:dda15c0a-b574-4ee8-b2a2-da84f7ace9dc">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">75</font></div>
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    </div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM</div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">To the Stockholders and </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">Board of Directors </font>of Ionis Pharmaceuticals, Inc.</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z93db58e58a264b7d9803fc7228e5ec7b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 98.31%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Opinion on Internal Control over Financial Reporting</font></div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have audited Ionis Pharmaceuticals, Inc.&#8217;s internal control over financial reporting as of December 31, 2018, based on criteria
                established in Internal Control-Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 Framework) (the COSO criteria). In our opinion, Ionis Pharmaceuticals, Inc. (the Company) maintained,
                in all material respects, effective internal control over financial reporting as of December 31, 2018, based on the COSO criteria.</font></div>
            <div>&#160;</div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the
                consolidated balance sheets of Ionis Pharmaceuticals, Inc. as of December 31, 2018 and 2017, and the related consolidated statements of operations, comprehensive income (loss), stockholders&#8217; equity and cash flows for each of the three years
                in the period ended December 31, 2018, and the related notes and our report dated March 1, 2019 expressed an unqualified opinion thereon.</font></div>
            <div>&#160;</div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Basis for Opinion</font></div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The Company&#8217;s management is responsible for maintaining effective internal control over financial reporting and for its assessment of
                the effectiveness of internal control over financial reporting included in the accompanying Management&#8217;s Report on Internal Control over Financial Reporting. Our responsibility is to express an opinion on the Company&#8217;s internal control over
                financial reporting based on our audit. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules
                and regulations of the Securities and Exchange Commission and the PCAOB.</font></div>
            <div>&#160;</div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We conducted our audit in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to
                obtain reasonable assurance about whether effective internal control over financial reporting was maintained in all material respects.</font></div>
            <div>&#160;</div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our audit included obtaining an understanding of internal control over financial reporting, assessing the risk that a material
                weakness exists, testing and evaluating the design and operating effectiveness of internal control based on the assessed risk, and performing such other procedures as we considered necessary in the circumstances. We believe that our audit
                provides a reasonable basis for our opinion.</font></div>
            <div>&#160;</div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Definition and Limitations of Internal Control Over Financial Reporting</font></div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A company&#8217;s internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability
                of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. A company&#8217;s internal control over financial reporting includes those policies and
                procedures that (1) pertain to the maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions and dispositions of the assets of the company; (2) provide reasonable assurance that transactions are
                recorded as necessary to permit preparation of financial statements in accordance with generally accepted accounting principles, and that receipts and expenditures of the company are being made only in accordance with authorizations of
                management and directors of the company; and (3) provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use, or disposition of the company&#8217;s assets that could have a material effect on the
                financial statements.</font></div>
            <div>&#160;</div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements.&#160; Also,
                projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.</font></div>
            <div>&#160;</div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;/s/ Ernst &amp; Young LLP</font></div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> </font>&#160;</div>
            <div>&#160;</div>
          </td>
          <td style="width: 1.69%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 98.31%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">San Diego, California</font></div>
          </td>
          <td style="width: 1.69%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 1pt;">&#160;</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 98.31%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">March 1, 2019</font></div>
          </td>
          <td style="width: 1.69%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 1pt;">&#160;</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:26033fdb-6f32-4711-ab17-d26dfd8cda5d">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">76</font></div>
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    </div>
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Item 9B. Other Information</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Not applicable.</font></div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">PART III</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 10. Directors, Executive Officers and Corporate Governance</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We incorporate by reference the information
          required by this Item with respect to directors and the Audit Committee from the information under the caption &#8220;ELECTION OF DIRECTORS,&#8221; including in particular the information under &#8220;Nominating, Governance and Review Committee&#8221; and &#8220;Audit
          Committee,&#8221; contained in our definitive Proxy Statement, which we will file with the Securities and Exchange Commission within 120 days after the end of the fiscal year ended </font>December 31, 2018<font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;"> (the &#8220;Proxy Statement&#8221;).</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We incorporate by reference the required information concerning our Code of Ethics from the information under the caption
        &#8220;Code of Ethics and Business Conduct&#8221; contained in the Proxy Statement. Our Code of Ethics and Business Conduct is posted on our website at www.ionispharma.com<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">(1)</sup>. We intend to disclose future amendments to, or waivers from, our Code of
        Ethics and Business Conduct on our website.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Section 16(a) Beneficial Ownership Reporting Compliance</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Item 1, Part&#160;I of this Report contains information concerning our executive officers. We incorporate by reference the
        information required by this Item concerning compliance with Section&#160;16(a)&#160;of the Exchange Act from the information under the caption &#8220;Section&#160;16(a)&#160;Beneficial Ownership Reporting Compliance&#8221; contained in the Proxy Statement.</font></div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;________________</font></div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z3f0c2420947348778ace36a6ab0b121a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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            <td style="width: 18pt; vertical-align: top; align: right;">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Any information that is included on or linked to our website is not part of this Form 10-K.</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 11. Executive Compensation</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We incorporate by reference the information required by this item to the information under the caption &#8220;EXECUTIVE
        COMPENSATION,&#8221; &#8220;Compensation Committee Interlocks and Insider Participation&#8221; and &#8220;COMPENSATION COMMITTEE REPORT&#8221; contained in the Proxy Statement.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We incorporate by reference the information required by this item to the information under the captions &#8220;SECURITY
        OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT&#8221; contained in the Proxy Statement.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Securities Authorized for Issuance under Equity Compensation Plans</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table sets forth information regarding outstanding options and shares reserved for future issuance under our
        equity compensation plans as of December 31, 2018.</font></div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <table cellspacing="0" cellpadding="0" border="0" id="z9c5aeb04bd1d4756a6246e33bd91c88e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; width: 63%;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Plan&#160;Category</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; width: 1%;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="2" style="vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Number of Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">to be Issued</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Upon Exercise of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Outstanding Options</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; width: 1%;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; width: 1%;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="2" style="vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted Average</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Exercise Price of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Outstanding Options</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; width: 1%;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; width: 1%;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="2" style="vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Number of Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Remaining</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Available for</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Future Issuance</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; width: 1%;">&#160;</td>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; width: 1%;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 63%; padding-bottom: 2px; background-color: rgb(204, 238, 255);">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Equity compensation plans approved by stockholders(a)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,311,944</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">47.85</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,578,854</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(b)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 63%; padding-bottom: 4px; background-color: rgb(255, 255, 255);">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,311,944</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">47.85</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,578,854</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
        </tr>

    </table>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;________________</font></div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z5972ff27253c495a8a3d3813701a03f1" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(a)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consists of four Ionis plans: 1989 Stock Option Plan, Amended and Restated 2002 Non-Employee Directors&#8217; Stock Option Plan, 2011 Equity Incentive Plan and
                    Employee Stock Purchase Plan, or ESPP.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left; text-indent: -36pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="ze09be45cf7ca4cae8406350bf9d8a6f9" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(b)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Of these shares, 774,816 remained available for purchase under the ESPP as of December 31, 2018. The ESPP incorporates an evergreen formula pursuant to which
                    on January&#160;1 of each year on the first nine anniversaries of the plan, we automatically increase the aggregate number of shares reserved for issuance under the plan by 150,000 shares.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For additional details about our equity compensation plans, including a description of each plan, see Note 4, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Stockholders&#8217; Equity</font>, in the Notes to the Consolidated Financial Statements.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 13. Certain Relationships and Related Transactions, and Director Independence</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We incorporate by reference the information required by this item to the information under the captions &#8220;Independence of
        the Board of Directors&#8221; and &#8220;Certain Relationships and Related Transactions&#8221; contained in the Proxy Statement.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 14. Principal Accounting Fees and Services</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We incorporate by reference the information required by this item to the information under the caption &#8220;Ratification of
        Selection of Independent Auditors&#8221; contained in the Proxy Statement.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">77</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">PART IV</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 15. Exhibits, Financial Statement Schedules</font></div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: left; text-indent: -36pt; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(a)(1) Index to Financial Statements</font></div>
    <div style="text-align: justify; text-indent: -36pt; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We submitted the consolidated financial statements required by this item in a separate section beginning on page&#160;F-1 of
        this Report.</font></div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: left; text-indent: -36pt; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(a)(2) Index to Financial Statement Schedules</font></div>
    <div style="text-align: left; text-indent: -36pt; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We omitted these schedules because they are not required, or are not applicable, or the required information is shown in
        the consolidated financial statements or notes thereto.</font></div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: left; text-indent: -36pt; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(a)(3) Index to Exhibits</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:0965a9ef-85ad-4f9f-b2ea-a12215eb16b7">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">78</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">INDEX TO EXHIBITS</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z13f9cf712f5a43b4b987afce12ac2623" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 7.37%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Exhibit Number</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom;">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Description of Document</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3.1</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401518000047/exhibit3_1.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Amended and Restated Certificate of Incorporation filed June 19, 1991</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s
                  Annual Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3.2</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036114017588/formdef14a.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Certificate of Amendment to Restated Certificate of Incorporation</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, </font><font style="font-size: 10pt;
                  font-family: 'Times New Roman', Times, serif;">filed June 17, 2014. - Filed as an exhibit to the Registrant&#8217;s Notice of Annual Meeting and Proxy Statement, for the 2014 Annual Meeting of Stockholders, filed with the SEC on April 25, 2014,
                  and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3.3</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036115045083/ex3_1.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Certificate of Amendment to Restated Certificate of Incorporation</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, </font><font style="font-size: 10pt;
                  font-family: 'Times New Roman', Times, serif;">filed December 18, 2015. - Filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed December 18, 2015 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3.4</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036115045083/ex3_2.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Amended and Restated Bylaws</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed December 18,
                  2015 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4.1</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000091205700053343/a2032851zex-4_2.txt"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Certificate of Designation of the Series C Junior Participating Preferred Stock</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit
                  to Registrant&#8217;s Report on Form 8-K dated filed December 13, 2000 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4.2</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401518000047/exhibit4_2.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Specimen Common Stock Certificate</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year
                  ended December 31, 2017 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4.3</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465912057327/a12-17479_3ex4d1.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Indenture, dated as of August 13, 2012, between the Registrant and Wells Fargo Bank, National Association, as trustee, including Form of 2&#190; percent Convertible Senior Note due 2019</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Report on Form 8-K filed August 13, 2012 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4.4</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465914082750/a14-24885_1ex4d1.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Indenture, dated as of November 17, 2014, between the Registrant and Wells Fargo Bank, National Association, as trustee, including Form of 1.00 percent Convertible Senior Note due 2021</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed November 21, 2014 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.1</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465913016208/a12-28450_1ex10d1.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Form of Indemnity Agreement entered into between the Registrant and its Directors and Officers with related schedule</font></a><font style="font-size: 10pt; font-family: 'Times New Roman',
                  Times, serif;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2012 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.2*</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465912025639/a12-1729_1def14a.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Registrant&#8217;s 1989 Stock Option Plan, as amended</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to Registrant&#8217;s Notice of Annual
                  Meeting and Proxy Statement for the 2012 Annual Meeting of Stockholders, filed with the SEC on April 16, 2012, and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.3*</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465909024876/a09-2041_1def14a.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Registrant&#8217;s Amended and Restated 2000 Employee Stock Purchase Plan</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to
                  Registrant&#8217;s Notice of Annual Meeting and Proxy Statement for the 2009 Annual Meeting of Stockholders, filed with the SEC on April 20, 2009, and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.4</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401518000047/exhibit10_4.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Form of Employee Confidential Information and Inventions Agreement</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Annual
                  Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.5</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000091205701527777/a2056057zex-10_2.txt"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Collaboration and License Agreement between the Registrant and Hybridon, Inc., dated May 24, 2001</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">,
                  filed as an exhibit to the Registrant&#8217;s report on Form 10-Q as amended for the quarter ended June 30, 2001 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request
                  for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.6</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465911044376/a11-13864_1ex10d1.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Amendment #1 to the Research, Development and License Agreement dated May 11, 2011 by and between the Registrant and Glaxo Group Limited</font></a><font style="font-size: 10pt; font-family:
                  'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2011 and incorporated herein by reference. Portions of this exhibit have been omitted and separately
                  filed with the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.7</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465908032466/a08-11587_1ex10d2.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Amended and Restated Collaboration and License Agreement between the Registrant and Antisense Therapeutics Ltd dated February 8, 2008</font></a><font style="font-size: 10pt; font-family:
                  'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2008 and incorporated herein by reference. Portions of this exhibit have been omitted and separately
                  filed with the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.37%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.8</font></div>
          </td>
          <td colspan="2" style="width: 2.19%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td colspan="2" style="width: 90.44%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465910010939/a09-34643_2ex10d13.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Amended and Restated License Agreement between the Registrant and Atlantic Pharmaceuticals Limited dated November 30, 2009</font></a><font style="font-size: 10pt; font-family: 'Times New
                  Roman', Times, serif;">, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">filed as an exhibit to the Registrant&#8217;s Annual Report as Form 10-K for the year ended December 31, 2009 and incorporated herein
                  by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>

    </table>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">79</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z9746c5d0109244d1be4e22aaa56a1e9d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.9</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401517000033/ex10_2.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Stock Purchase Agreement among the Registrant, Akcea Therapeutics, Inc. and Novartis Pharma AG</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> dated January 5,
                  2017, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2017 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.10</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401517000033/ex10_3.htm"><font style="font-size: 10pt; font-family:
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                  Quarterly Report on Form 10-Q for the quarter ended March 31, 2017 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.11</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465913081234/a13-19600_1ex10d4.htm"><font style="font-size: 10pt;
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                  to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2013 and incorporated herein by reference.</font></font></div>
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        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
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          </td>
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    </table>
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    <table cellspacing="0" cellpadding="0" id="z5537666ac7d649bc96fdd409849bb3f8" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.13*</font></div>
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          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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                    font-family: 'Times New Roman', Times, serif;">Form of Restricted Stock Unit Agreement for Restricted Stock Units granted under the Ionis Pharmaceuticals, Inc. Amended and Restated 2002 Non-Employee Directors&#8217; Stock Option Plan</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2012 and incorporated herein by reference.</font></font></div>
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        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.14</font></div>
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          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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                  December 19, 2017, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC
                  with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.15*</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465911023713/a11-2831_1def14a.htm"><font style="font-size: 10pt;
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                  Notice of 2011 Annual Meeting of Stockholders and Proxy Statement filed with the SEC on April 28, 2011, and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.16*</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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                  Report on Form 10-Q for the quarter ended September 30, 2015 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.17*</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465911044856/a11-23763_1ex99d3.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Form of Restricted Stock Unit Agreement for Restricted Stock Units granted under the 2011 Equity Incentive Plan</font></a><font style="font-size: 10pt; font-family: 'Times New Roman',
                  Times, serif;">, filed as an exhibit to the Registrant&#8217;s Registration Statement on Form S-8 filed with the SEC on August 8, 2011, and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.18</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036117028398/ex10_1.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Loan Agreement between Ionis Gazelle, LLC and UBS AG dated July 18, 2017</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s
                  Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.19*</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401515000082/ex10_5.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Form of Option Agreement under the 1989 Stock Option Plan</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Quarterly
                  Report on Form 10-Q for the quarter ended September 30, 2015 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.20*</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000104746905006784/a2153640zex-10_57.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Form of Option Agreement for Options Granted after March 8, 2005 under the 2002 Non-Employee Director&#8217;s Stock Option Plan</font></a><font style="font-size: 10pt; font-family: 'Times New
                  Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2004 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.21</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465910026849/a10-5958_1ex10d5.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Research, Development and License Agreement between the Registrant and Glaxo Group Limited dated March 30, 2010</font></a><font style="font-size: 10pt; font-family: 'Times New Roman',
                  Times, serif;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2010 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC
                  with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.22</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036117028398/ex10_2.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Loan Agreement between Ionis Faraday, LLC and UBS AG</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> dated July 18, 2017, filed as an exhibit to the Registrant&#8217;s
                  Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.23</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465911061713/a11-25667_1ex10d1.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Research Agreement dated August 10, 2011 between the Registrant and CHDI Foundation, Inc</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an
                  exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2011 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for
                  confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.24</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036117028398/ex10_3.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Guaranty between the Registrant and UBS AG</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> dated July 18, 2017, filed as an exhibit to the Registrant&#8217;s Current
                  Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.25</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465912034636/a12-6491_1ex10d1.htm"><font style="font-size: 10pt;
                    font-family: 'Times New Roman', Times, serif;">Development, Option and License Agreement between the Registrant and Biogen Idec International Holding Ltd. dated January 3, 2012</font></a><font style="font-size: 10pt; font-family: 'Times
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          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>

    </table>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">80</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z6e01abae28794697bd736fb7d14a7e3b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.26</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.27</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
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          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
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    </table>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.29</font></div>
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          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
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          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
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        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
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                  confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000110465913081234/a13-19600_1ex10d2.htm"><font style="font-size: 10pt;
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                  filed with the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
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        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.33</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036114018974/ex10_1.htm"><font style="font-size: 10pt; font-family:
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                  filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2014 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request
                  for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.34</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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                    'Times New Roman', Times, serif;">Amendment No. 3 to the Research, Development and License Agreement between the Registrant and Glaxo Group Limited dated July 10, 2013</font></a><font style="font-size: 10pt; font-family: 'Times New
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                  the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.35</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036114030549/ex10_2.htm"><font style="font-size: 10pt; font-family:
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                  the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.36</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036114030549/ex10_3.htm"><font style="font-size: 10pt; font-family:
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                  exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.37</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401514000095/ex10_1.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Exclusive License Agreement between the Registrant and the University of Massachusetts dated January 14, 2010</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">,
                  filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a
                  request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.38</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401514000095/ex10_2.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Amended and Restated Collaboration and License Agreement between the Registrant and Cold Spring Harbor Laboratory dated October 26, 2011</font></a><font style="font-size: 10pt; font-family: 'Times New
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          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.39</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401514000095/ex10_3.htm"><font style="font-size: 10pt; font-family:
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          </td>
        </tr>

    </table>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">81</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div><br>
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    <table cellspacing="0" cellpadding="0" id="zee37125f39724683a201f3b996c8389f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.40</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.44</font></div>
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          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.45</font></div>
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          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.64%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.46</font></div>
          </td>
          <td style="width: 2.09%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.27%; vertical-align: top; background-color: rgb(204, 238, 255);">
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                    'Times New Roman', Times, serif;">License Agreement between the Registrant and Bayer Pharma AG dated May 1, 2015. Portions of this exhibit have been omitted and separately filed with the SEC</font></a><font style="font-size: 10pt;
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          </td>
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    </table>
    <div><br>
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    <table cellspacing="0" cellpadding="0" id="z802770fc171c4acfad20d22929c49f7c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.47</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401515000077/ex10_2.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Line of Credit Agreement between the Registrant and Morgan Stanley Private Bank, National Association dated June 16, 2015</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times,
                  serif;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2015 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.48</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401515000057/ex10_1.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Second Amended and Restated Strategic Collaboration and License Agreement between the Registrant and Alnylam Pharmaceuticals, Inc. dated January 8, 2015</font></a><font style="font-size: 10pt;
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                  and separately filed with the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.49</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401515000057/ex10_2.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Amendment #1 to HTT Research, Development, Option and License Agreement between the Registrant, F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc. dated January 9, 2015</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2015 and incorporated herein by reference. Portions of this
                  exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.50</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036116046574/ex10_1.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Amendment No.1 to Loan Documents between the Registrant and Morgan Stanley Private Bank, National Association dated December 30, 2015</font></a><font style="font-size: 10pt; font-family: 'Times New
                  Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed January 5, 2016 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.51</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401516000112/ex10_64.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Amendment No.2 to Line of Credit Agreement between the Registrant and Morgan Stanley Private Bank, National Association dated February 24, 2016</font></a><font style="font-size: 10pt; font-family:
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          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.52</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401516000118/ex10_1.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Amendment No.3 to the Collaboration, License and Development Agreement between the Registrant and AstraZeneca AB dated January 18, 2016</font></a><font style="font-size: 10pt; font-family: 'Times New
                  Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2016 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with
                  the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.53</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401516000118/ex10_2.htm"><font style="font-size: 10pt; font-family:
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          </td>
        </tr>

    </table>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman', Times, serif; font-size: 8pt; font-weight: normal; font-style: normal;">82</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div><br>
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    <table cellspacing="0" cellpadding="0" id="z5e1f496dea5d4a9fb5e4a8f2c02ba4e3" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.54</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
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                  font-family: 'Times New Roman', Times, serif;">,</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2016
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          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.55</font></div>
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          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.56</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
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        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.57</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
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          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
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                  as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.</font></font></div>
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        </tr>
        <tr>
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          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
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          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
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                    'Times New Roman', Times, serif;">Amendment to Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, filed as an exhibit to the Registrant&#8217;s
                  Notice of Annual Meeting and Proxy Statement, for the 2017 Annual Meeting of Stockholders, filed with the SEC on April 10, 2017, and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.60*</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
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                    'Times New Roman', Times, serif;">Registrant&#8217;s Severance Benefit Plan and Summary Plan Description dated October 18, 2018</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, - filed as an exhibit to
                  the Registrant&#8217;s Current Report on form 8-K filed October 18, 2018 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.61</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
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                    'Times New Roman', Times, serif;">Strategic Advisory Services Agreement by and between the Registrant and B. Lynne Parshall,</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> dated January 15, 2018,
                  filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2018 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.62</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
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                    'Times New Roman', Times, serif;">Development, Commercialization, Collaboration, and License Agreement by and between the Registrant and Akcea Therapeutics, Inc.</font></a><font style="font-size: 10pt; font-family: 'Times New Roman',
                  Times, serif;">, dated March 14, 2018, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2018 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.63</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401518000060/ex10_3.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Amended and Restated Services Agreement by and between the Registrant and Akcea Therapeutics, Inc.</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, dated March
                  14, 2018, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended March 31, 2018 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.64</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401518000105/ex10_1.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc.</font></a><font style="font-size: 10pt; font-family:
                  'Times New Roman', Times, serif;">, dated April 19, 2018, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2018 and incorporated herein by reference. Portions of this exhibit have been
                  omitted and separately filed with the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.65</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401518000105/ex10_2.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Stock Purchase Agreement by and between the Registrant and Biogen MA Inc.</font></a><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, dated April 19, 2018, filed as an
                  exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended June 30, 2018 and incorporated herein by reference.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.66</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000087401518000128/ex10_1.htm"><font style="font-size: 10pt; font-family:
                    'Times New Roman', Times, serif;">Second Amendment to Research, Collaboration, Option and License Agreement by and between the Registrant and Janssen Biotech Inc.</font></a><font style="font-size: 10pt; font-family: 'Times New Roman',
                  Times, serif;">, dated August 7, 2018, filed as an exhibit to the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarter ended September 30, 2018 and incorporated herein by reference. Portions of this exhibit have been omitted and
                  separately filed with the SEC with a request for confidential treatment.</font></font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><a href="exhibit10_67.htm"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.67</font></font></a></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Factor B Development Collaboration, Option and License Agreement by and between the Registrant, F. Hoffmann-La Roche Ltd and
                Hoffmann-La Roche Inc., dated October 9, 2018. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><a href="exhibit10_68.htm"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.68</font></font></a></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and
                between the Registrant and Biogen MA Inc, dated October 17, 2018. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><a href="exhibit10_69.htm"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.69</font></font></a></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Amendment #1 to the Strategic Collaboration Agreement by and between the Registrant and AstraZeneca AB, dated October 18, 2018.
                Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><a href="exhibit10_70.htm"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.70</font></font></a></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Amendment #4 to the Collaboration, License and Development Agreement by and between the Registrant and AstraZeneca AB, dated October
                18, 2018. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><a href="exhibit21_1.htm"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21.1</font></font></a></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">List of Subsidiaries for the Registrant.</font></div>
          </td>
        </tr>

    </table>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
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      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z3fb3dce3914c451492a6773ce4928a05" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><a href="exhibit23_1.htm"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">23.1</font></font></a></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consent of Independent Registered Public Accounting Firm.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24.1</font></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Power of Attorney &#8211; Included on the signature page of this Annual Report on Form 10-K.</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><a href="exhibit31_1.htm"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">31.1</font></font></a></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Certification by Chief Executive Officer Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 302 of the Sarbanes-Oxley
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          </td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
        </tr>
        <tr>
          <td style="width: 7.81%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><a href="exhibit31_2.htm"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">31.2</font></font></a></div>
          </td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Certification by Chief Financial Officer Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 302 of the Sarbanes-Oxley
                Act of 2002.</font></div>
          </td>
        </tr>
        <tr>
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            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Certification Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.</font></div>
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          <td style="width: 7.81%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 2%; vertical-align: bottom; background-color: rgb(255, 255, 255);">&#160;</td>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">101</font></div>
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          <td style="width: 90.19%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following financial statements from the Ionis Pharmaceuticals, Inc. Annual Report on Form 10-K for the year ended December 31,
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Indicates management compensatory plans and arrangements as required to be filed as exhibits to this Report pursuant to Item 14(c).</font></div>
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">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
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">SIGNATURES</div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the Registrant has duly caused
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS PHARMACEUTICALS,&#160;INC.</font></div>
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          <td style="width: 49.86%; vertical-align: top;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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          <td style="width: 4.14%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td style="width: 46%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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          <td style="width: 49.86%; vertical-align: top;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">By:</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">/s/ STANLEY T. CROOKE</font></div>
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          <td style="width: 4.14%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Stanley T. Crooke, M.D., Ph.D.</font></div>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">POWER OF ATTORNEY</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">KNOW ALL MEN BY THESE PRESENTS, that each person whose signature appears below constitutes and appoints Stanley T. Crooke
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Pursuant to the requirements of the Securities Exchange Act of 1934, this report has been signed below by the following
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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          <td style="width: 48.21%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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          <td style="width: 2.19%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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          <td style="width: 17.81%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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          <td style="width: 29.79%; vertical-align: top; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">/s/ STANLEY T. CROOKE</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
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          <td style="width: 2.19%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 17.81%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">March 1, 2019</font></div>
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        <tr>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Stanley T. Crooke, M.D., Ph.D.</font></div>
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          <td style="width: 2%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(Principal executive officer)</font></div>
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          <td style="width: 2.19%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
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          <td style="width: 17.81%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
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          <td style="width: 29.79%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 2%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 48.21%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 2.19%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 17.81%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">/s/ ELIZABETH L. HOUGEN</font></div>
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          <td style="width: 2%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Senior Vice President, Finance and Chief Financial Officer</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 17.81%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">March 1, 2019</font></div>
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        <tr>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Elizabeth L. Hougen</font></div>
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          <td style="width: 2%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(Principal financial and accounting officer)</font></div>
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          <td style="width: 2.19%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 17.81%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
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          <td style="width: 29.79%; vertical-align: top;">&#160;</td>
          <td style="width: 2%; vertical-align: top;">&#160;</td>
          <td style="width: 48.21%; vertical-align: top;">&#160;</td>
          <td style="width: 2.19%; vertical-align: top;">&#160;</td>
          <td style="width: 17.81%; vertical-align: top;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">/s/ B. LYNNE PARSHALL</font></div>
          </td>
          <td style="width: 2%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Director and Senior Strategic Advisor</font></div>
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          <td style="width: 2.19%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 17.81%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">March 1, 2019</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 29.79%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">B. Lynne Parshall, J.D.</font></div>
          </td>
          <td style="width: 2%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 48.21%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 2.19%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 17.81%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
        </tr>
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          <td style="width: 29.79%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td style="width: 2%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td style="width: 48.21%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td style="width: 2.19%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td style="width: 17.81%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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        <tr>
          <td style="width: 29.79%; vertical-align: top; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">/s/ SPENCER R. BERTHELSEN</font></div>
          </td>
          <td style="width: 2%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
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          <td style="width: 48.21%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Director</font></div>
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          <td style="width: 2.19%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 17.81%; vertical-align: top;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">March 1, 2019</font></div>
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        <tr>
          <td style="width: 29.79%; vertical-align: top;">
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS,&#160;INC.</div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">INDEX TO CONSOLIDATED FINANCIAL STATEMENTS</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <table cellspacing="0" cellpadding="0" id="z6a3da2b4fed74d0f85f7b963ada945ce" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font></div>
          </td>
          <td style="width: 6.61%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Page</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 93.39%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Report of Independent Registered Public Accounting Firm</font></div>
          </td>
          <td style="width: 6.61%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">F-2</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 93.39%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consolidated Balance Sheets at December 31, 2018 and 2017 (as revised)</font></div>
          </td>
          <td style="width: 6.61%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">F-3</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 93.39%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consolidated Statements of Operations for the years ended December 31, 2018, 2017 and 2016 (as revised)</font></div>
          </td>
          <td style="width: 6.61%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">F-4</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 93.39%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consolidated Statements of Comprehensive Loss for the years ended December 31, 2018, 2017 and 2016 (as revised)</font></div>
          </td>
          <td style="width: 6.61%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">F-5</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 93.39%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consolidated Statements of Stockholders&#8217; Equity for the years ended December 31, 2018, 2017 and 2016 (as revised)</font></div>
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          <td style="width: 6.61%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">F-6</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 93.39%; vertical-align: top; background-color: rgb(255, 255, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Consolidated Statements of Cash Flows for the years ended December 31, 2018, 2017 and 2016 (as revised)</font></div>
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          <td style="width: 6.61%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">F-7</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 93.39%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Notes to Consolidated Financial Statements</font></div>
          </td>
          <td style="width: 6.61%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">F-9</font></div>
          </td>
        </tr>

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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM</div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: left;">
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">To the Stockholders and </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt;
            font-family: 'Times New Roman', Times, serif;">Board of Directors </font>of Ionis Pharmaceuticals, Inc.</font></div>
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    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Opinion on the Financial Statements</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have audited the accompanying consolidated balance sheets of Ionis Pharmaceuticals, Inc. (the Company) as of December 31, 2018 and 2017,
        the related consolidated statements of operations, comprehensive income (loss), stockholders&#8217; equity and cash flows for each of the three years in the period ended December 31, 2018, and the related notes (collectively referred to as the
        &#8220;consolidated financial statements&#8221;). In our opinion, the consolidated financial statements present fairly, in all material respects, the financial position of the Company at December 31, 2018 and 2017, and the results of its operations and its
        cash flows for each of the three years in the period ended December 31, 2018, in conformity with U.S. generally accepted accounting principles.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the
        Company&#8217;s internal control over financial reporting as of December 31, 2018, based on criteria established in Internal Control-Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 Framework), and
        our report dated March 1, 2019 expressed an unqualified opinion thereon.</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adoption of ASU No. 2014-09, Revenue Recognition</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As discussed in Note 1 to the consolidated financial statements, the Company changed its method of accounting for revenue for all years
        presented, 2016 through 2018, due to the adoption of ASU No. 2014-09, Revenue from Contracts with Customers (Topic 606).</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Basis for Opinion</font></div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">These financial statements are the responsibility of the Company's management. Our responsibility is to express an opinion on the Company&#8217;s
        financial statements based on our audits. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and
        regulations of the Securities and Exchange Commission and the PCAOB.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain
        reasonable assurance about whether the financial statements are free of material misstatement, whether due to error or fraud. Our audits included performing procedures to assess the risks of material misstatement of the financial statements,
        whether due to error or fraud, and performing procedures that respond to those risks. Such procedures included examining, on a test basis, evidence regarding the amounts and disclosures in the financial statements. Our audits also included
        evaluating the accounting principles used and significant estimates made by management, as well as evaluating the overall presentation of the financial statements. We believe that our audits provide a reasonable basis for our opinion.</font></div>
    <div><br>
    </div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">/s/ Ernst &amp; Young LLP</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have served as the Company&#8217;s auditor since 1989</font></div>
    <div><br>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">San Diego, California</font></div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">March 1, 2019</font></div>
    <div><br>
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">CONSOLIDATED BALANCE SHEETS</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(In thousands, except share data)</font></div>
    <div><br>
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    <table cellspacing="0" cellpadding="0" id="z4a8dc47380994b248d0d8bdfba7c7e41" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: center; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ASSETS</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised*)</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current assets:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">278,820</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">129,630</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Short-term investments</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,805,252</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">893,085</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Contracts receivable</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,759</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">62,955</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Inventories</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,582</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,982</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other current assets</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">102,473</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">73,082</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total current assets</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,168,734</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Property, plant and equipment, net</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">132,160</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">121,907</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Patents, net</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24,032</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,004</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term deferred tax assets</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">290,796</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deposits and other assets</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,910</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,129</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total assets</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,667,784</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,322,774</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: center; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">LIABILITIES





                  AND STOCKHOLDERS</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> EQUITY</font></font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current liabilities:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accounts payable</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">28,660</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24,886</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accrued compensation</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">29,268</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">25,151</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accrued liabilities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48,361</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">66,618</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current portion of long-term obligations</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13,749</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,621</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current portion of deferred contract revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">160,256</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">125,336</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total current liabilities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">280,294</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">243,612</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">567,359</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,026</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">568,215</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">533,111</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term obligations, less current portion</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,914</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,974</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -36pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term mortgage debt</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">59,842</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">59,771</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total liabilities</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,480,624</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">957,494</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Stockholders&#8217; equity:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Common stock, $0.001 par value; 300,000,000 shares authorized, 137,928,828 and 124,976,373 shares
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">138</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">125</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additional paid-in capital</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,047,250</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,553,681</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accumulated other comprehensive loss</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(32,016</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(31,759</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accumulated deficit</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(967,293</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,241,034</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total Ionis stockholders&#8217; equity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,048,079</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">281,013</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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: -18.15pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Noncontrolling interest in Akcea Therapeutics, Inc.</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">139,081</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,267</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total stockholders&#8217; equity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,187,160</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">365,280</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total liabilities and stockholders&#8217; equity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,667,784</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,322,774</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

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    <div style="text-align: justify;">
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        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z988915eef5da4f6f9b65186047f7f791" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our 2017 amounts are revised to reflect the new revenue recognition accounting guidance, which we adopted retrospectively in the first quarter of 2018. Refer
                    to Note 1,<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"> Organization and Significant Accounting Policies</font>, for further information.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">See accompanying notes.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:4646739c-83dd-4a6d-9b8f-c5ec2e3f4827">
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">CONSOLIDATED STATEMENTS OF OPERATIONS</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(In thousands, except for per share amounts)</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised*)</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">237,930</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112,540</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">883</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI product sales, net</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,237</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Licensing and other royalty revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,755</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,474</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,884</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total commercial revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">254,922</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120,014</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,767</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research and development revenue under collaborative agreements</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">344,752</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">394,165</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">350,009</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">599,674</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">514,179</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">372,776</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expenses:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cost of products sold</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research, development and patent</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selling, general and administrative</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">244,622</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,488</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48,616</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total operating expenses</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">483,132</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">392,936</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income (loss) from operations</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(20,160</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Investment income</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,187</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,179</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5,472</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Interest expense</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(44,789</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(44,752</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(38,795</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Loss on extinguishment of financing liability for leased facility</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,129</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">273,741</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">346</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net income (loss) per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.09</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.15</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.50</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares used in computing basic net income (loss) per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">132,320</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">124,016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120,933</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Diluted net income (loss) per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.07</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.15</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.50</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares used in computing diluted net income (loss) per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">134,056</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">126,098</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120,933</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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    </div>
    <div style="text-align: justify;">
      <div>
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            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">*</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our 2017 and 2016 amounts are revised to reflect the new revenue recognition accounting guidance, which we adopted retrospectively in the first quarter of
                    2018. Refer to Note 1,<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"> Organization and Significant Accounting Policies</font>, for further information.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">See accompanying notes.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:8237c38a-30a8-449e-8b63-ac3872115896">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-4</font></div>
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">I<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">ONIS PHARMACEUTICALS, INC.</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">CONSOLIDATED STATEMENTS OF COMPREHENSIVE INCOME (LOSS)</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(In thousands)</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zc867250241bb4f37a1af29b029c89cb5" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised*)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">214,985</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(10,783</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(960</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Reclassification adjustment for realized (gains) losses included in net loss</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">447</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Currency translation adjustment</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">23</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(67</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(21</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Comprehensive income (loss)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">214,728</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,184</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(77,193</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Comprehensive loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(58,781</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(11,224</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Comprehensive income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">273,509</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(960</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(77,193</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z309757c09e47431eab3dbc64d399562a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">*</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our 2017 and 2016 amounts are revised to reflect the new revenue recognition accounting guidance, which we adopted retrospectively in the first quarter of
                    2018. Refer to Note 1,<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"> Organization and Significant Accounting Policies</font>, for further information.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">See accompanying notes.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:3b171950-caee-4b2e-afc9-84e9888521c6">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">CONSOLIDATED STATEMENTS OF STOCKHOLDERS</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> EQUITY</font></font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31, 2018, 2017 (*as revised) and 2016 (*as revised)</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(In thousands)</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z0c54dc3d773c4803baa59697ff1657a7" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Common Stock</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Additional Paid in</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Accumulated</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Other</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Comprehensive</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Accumulated</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Total Ionis</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Stockholders</font>&#8217;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Noncontrolling</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Interest in Akcea</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Stockholders</font>&#8217;</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Capital</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Loss</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Deficit</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Equity</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Therapeutics, Inc.</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Equity</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Balance at December 31, 2015</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120,351</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,309,107</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(13,565</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,094,872</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">200,790</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">200,790</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cumulative adjustment related to adopting Topic 606 revenue recognition guidance</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(86,108</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(86,108</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(86,108</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net loss</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(16,772</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(16,772</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(16,772</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Foreign currency translation</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(21</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(21</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(21</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Issuance of common stock in connection with employee stock plans</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,285</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13,706</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13,708</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13,708</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2&#190; percent convertible senior notes redemption, equity portion</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(128,888</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(128,888</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(128,888</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1 percent convertible senior notes, equity portion, net of issuance costs</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,335</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,335</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Stock-based compensation expense</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,108</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,108</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,108</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 20%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Excess tax benefits from stock-based compensation awards</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,861</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,861</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,861</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 20%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Balance at December 31, 2016</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">121,636</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">122</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,311,229</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(30,358</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,241,380</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">39,613</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">39,613</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(67</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(67</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Novartis stock purchase</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">71,737</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">71,739</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">71,739</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,709</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,931</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">157,270</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Noncontrolling interest in Akcea Therapeutics, Inc. in conjunction with initial public offering</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Noncontrolling interest in Akcea Therapeutics, Inc.</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(11,224</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Balance at December 31, 2017</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">125</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,553,681</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(31,759</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,241,034</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">281,013</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,267</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">365,280</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">273,741</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">273,741</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">273,741</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Change in unrealized gains (losses), net of tax</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(280</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(280</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(280</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 20%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Foreign currency translation</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">23</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">447,965</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">27,900</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">131,312</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">131,312</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">54,814</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(58,781</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 20%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Balance at December 31, 2018</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">137,929</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">138</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,047,250</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(32,016</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(967,293</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 7%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,048,079</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">139,081</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,187,160</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zbe7c9b0c6e9a448e8f5bf44a8c9a04ad" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">*</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our 2017 and 2016 amounts are revised to reflect the new revenue recognition accounting guidance, which we adopted retrospectively in the first quarter of
                    2018. Refer to Note 1,<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"> Organization and Significant Accounting Policies</font>, for further information.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">See accompanying notes.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:3fdb6059-3efc-4c4c-9890-5183595087d1">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-6</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-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">CONSOLIDATED STATEMENTS OF CASH FLOWS</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(In thousands)</font></div>
    <div><br>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised*)</font></font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Operating activities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">214,985</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(10,783</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Depreciation</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,706</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,708</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,481</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Amortization of patents</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,822</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,641</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,552</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">131,312</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(290,516</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,302</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,297</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">47,595</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">45,088</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Inventories</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other current and long-term assets</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term income tax receivable</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(223</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(9,114</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accounts payable</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(655</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,784</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income taxes</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(710</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">435</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,069</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accrued compensation</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,117</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">965</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,121</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accrued liabilities and deferred rent</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,720</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">494,254</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,182</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(85,306</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net cash provided by (used in) operating activities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
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          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(13,608</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3,093</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4,421</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Purchase of strategic investments</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Proceeds from the sale of Regulus Therapeutics, Inc.</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,507</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,467</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
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          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(929,563</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(358,291</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">56,599</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Proceeds from equity, net</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Proceeds from the issuance of common stock to Biogen</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">447,965</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Proceeds from the issuance of common stock to Novartis</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Proceeds from borrowing on line of credit facility</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Proceeds from the sale of Akcea Therapeutics, Inc. common stock to Novartis in a private placement</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Offering costs paid</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Payment to settle financing liability for leased facility</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Excess tax benefits from stock-based compensation awards</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
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            <div style="text-align: left; text-indent: -9pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net cash provided by financing activities</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,394</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(44,112</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents at beginning of year</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">129,630</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,685</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">128,797</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents at end of year</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">278,820</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">129,630</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,685</font></div>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">CONSOLIDATED STATEMENTS OF CASH FLOWS</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(In thousands)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised*)</font></font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Supplemental disclosures of cash flow information:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Interest paid</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,592</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,035</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,313</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Supplemental disclosures of non-cash investing and financing activities:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,428</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,983</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,439</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,350</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1 percent convertible senior notes principal issued related to our December 2016 debt exchange</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">185,450</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2&#190;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>percent





                convertible senior notes principal extinguished related to our December 2016 debt exchange</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">61,099</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Unpaid deferred offering costs</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">291</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7dd9bbbc7af4480c84dc30d81aa961da" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">*</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our 2017 and 2016 amounts are revised to reflect the new revenue recognition accounting guidance, which we adopted retrospectively in the first quarter of
                    2018. Refer to Note 1,<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"> Organization and Significant Accounting Policies</font>, for further information.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">See accompanying notes.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:0cc730c7-4dea-4f9e-bdfb-b26810835e47">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-8</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">IONIS PHARMACEUTICALS,&#160;INC.</div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">NOTES TO CONSOLIDATED FINANCIAL STATEMENTS</font></div>
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  </div>
  <div id="TRGRSegment:e7fe87ca-4e0b-4d3f-8c36-7ed610c940d6">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">1. Organization and Significant Accounting Policies</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:4d77b6f2-73c4-4a76-af48-b3afbf332bc5">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basis of Presentation</div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In our consolidated financial statements we
          included the accounts of Ionis Pharmaceuticals,&#160;Inc. (&#8220;we&#8221;, &#8220;us&#8221; or &#8220;our&#8221;) and the consolidated results of our majority-owned affiliate,&#160;Akcea Therapeutics, Inc., which we formed in December 2014. In July 2017, Akcea completed an initial public
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        our ownership percentage to approximately 75 percent. We reflected the increase in our ownership in these financial statements. In the first quarter of 2019, Akcea will pay us a $75 million sublicense fee in Akcea common stock, as a result of
        Novartis&#8217; license of AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in February 2019. We will receive 2.8 million shares of Akcea common stock for the sublicense fee. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Refer to the
          noncontrolling interest in Akcea section in this note for further information related to our accounting for our investment in Akcea.</font></font></div>
    <div><br>
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  </div>
  <div id="TRGRSegment:b7bd77f4-ea4f-479b-b0f8-c971602cd676">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Organization and Business Activity</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation
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    <div><br>
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  <div id="TRGRSegment:28c55423-aec3-4379-8a43-bdb7804ed6db">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic and Diluted Net Income (Loss) per Share</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Basic net income (loss) per share</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common
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    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The calculation of total net income (loss) attributable to our common stockholders for 2018 and 2017 considered our net
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    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:2a21233d-d6a9-4ae0-8dce-bf8130f06927">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our basic net income per share for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2018</font>, was
      calculated as follows (in thousands, except per share amounts):</div>
    <div><br>
    </div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Average Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Owned in Akcea</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Net Income (Loss)</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Per Share</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis</font>&#8217;</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Common shares</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2.74</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(163,938</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s net loss attributable to our ownership</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(163,938</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis&#8217; stand-alone net income</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">440,806</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">276,868</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Weighted average shares outstanding</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">132,320</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net income per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.09</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:395da648-9419-428e-bbba-fafd116ecd6c">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Prior to Akcea&#8217;s IPO in July 2017, we owned Akcea series A convertible preferred stock, which included a six percent cumulative
      dividend. Upon completion of Akcea&#8217;s IPO in July 2017, our preferred stock was converted into common stock on a 1:1 basis. The preferred stock dividend was not paid at the IPO because the IPO was not a liquidation event or a change in control. During
      2017, Akcea used a two-class method to compute its net income (loss) per share because it had both common and preferred shares outstanding during the periods. The two-class method required Akcea to calculate its net income (loss) per share&#160;for each
      class of stock by dividing total distributable losses applicable to preferred and common stock, including the&#160;six percent&#160;cumulative dividend contractually due to series A convertible preferred shareholders, by the weighted-average of preferred and
      common shares outstanding during the requisite period. Since Akcea used the two-class method, accounting rules required us to include our portion of Akcea&#8217;s net income (loss) per share for both Akcea&#8217;s common and preferred shares that we owned in our
      calculation of basic and diluted net income (loss) per share for year ended December 31, 2017.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:2619a7e2-0fa2-4c11-92fd-b3e597198aed">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-9</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our basic net income per share for 2017 as follows (in thousands, except per share amounts):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="ze0ee53ac16694450b66ce291d7a7e350" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2017</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Average Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Owned in Akcea</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
                  10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Net Loss</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Per Share</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis</font>&#8217;</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Portion of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Common shares</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">20,669</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3.08</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(63,638</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Preferred shares</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15,748</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1.80</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s net loss attributable to our ownership</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(91,984</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis&#8217; stand-alone net income</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">110,776</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,792</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Weighted average shares outstanding</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">124,016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net income per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.15</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:1630637e-7310-449d-a657-fb123c4aa6d8">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Dilutive net income (loss per share)</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For 2018 and 2017, we had net income available to Ionis common stockholders. As a result, we computed diluted net income
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    </div>
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  <div id="TRGRSegment:b1887428-715b-48a6-b48a-08d0cc52d890">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our diluted net income per share for 2018 as follows <font style="font-size: 10pt; font-family: 'Times New Roman', Times,
        serif;">(in thousands except per share amounts):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z8bac0226b8a24a12a6bd2054fb7d0f1e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Income</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Numerator)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Denominator)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Per-Share</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Amount</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">276,868</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">132,320</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.09</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Effect of dilutive securities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable upon exercise of stock options</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,216</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable upon restricted stock award issuance</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">514</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable related to our ESPP</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income available to Ionis common stockholders, plus assumed conversions</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">276,868</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">134,056</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.07</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We calculated our diluted net income per share for 2017 as follows <font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;">(in thousands except per share amounts):</font></font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z7f473c6545184c258b1d752a46629fdc" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2017</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Income</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Numerator)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Denominator)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Per-Share</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Amount</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,792</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">124,016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.15</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Effect of dilutive securities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable upon exercise of stock options</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,619</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable upon restricted stock award issuance</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">459</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable related to our ESPP</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income available to Ionis common stockholders, plus assumed conversions</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,792</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">126,098</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.15</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:be88e5ee-5556-4644-b275-f715c64a76fd">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For 2018 and 2017, the calculation excluded our convertible notes because the effect on diluted earnings per share was anti-dilutive.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For 2016, 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:</font></div>
    <div><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zae71ac34fd8446029a976a466e2a527e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1 percent convertible senior notes;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7ad8b8e3f3b343d39d41fb2d5f032e75" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2&#190; percent convertible senior notes;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zdc8f690fee6c4958a704f82a82218e0e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
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              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z8ce89b67319448869182f32100e21714" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Unvested restricted stock units; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z0940361fa8fe443da42184c27621e4f8" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Employee Stock Purchase Plan, or ESPP.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:2270e124-0bd8-47d6-9509-eb30979452b0">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Revenue Recognition</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Adoption of New Revenue Recognition
            Accounting Standard (Topic 606)</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In May 2014, the FASB issued accounting guidance on the recognition of revenue from customers. <font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">This guidance supersedes the revenue recognition requirements we previously followed in Accounting Standards Codification, or ASC, Topic 605, </font><font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif; font-style: italic;">Revenue Recognition</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, or Topic 605, and created a new Topic 606, </font><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif; font-style: italic;">Revenue from Contracts with Customers</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, or Topic 606. </font>Under Topic 606, an entity will
        recognize revenue when it transfers control of promised goods or services to customers in an amount that reflects what the entity expects to receive in exchange for the goods or services. Further, an entity will recognize revenue upon satisfying
        the performance obligation(s) under the related contract. We adopted Topic 606 on January 1, 2018 under the full retrospective approach, which required us to revise our prior period revenue. Under Topic 606, we were required to review all of our
        ongoing collaboration agreements in which we recognized revenue after January 1, 2016. We were required to assess what our revenue would have been for the period from January 1, 2016 to December 31, 2017 under Topic 606. As a result of this
        analysis, we determined that the cumulative revenue we would have recognized under Topic 606 decreased by $86.1 million. We recorded this amount as a cumulative adjustment to our accumulated deficit as of January 1, 2016 on our revised statement of
        stockholders&#8217; equity. We have labeled our prior period financial statements &#8220;as revised&#8221; to indicate the change required under the accounting rules.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:b18aeff2-8d7b-4c5a-a556-6b6e2ca4e644">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-10</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following tables summarize the adjustments we were required to make to amounts we originally reported in 2017 and 2016 to adopt
      Topic 606 (in thousands, except per share amounts):</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Consolidated Balance Sheet</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z98bdbb63906c43d08f06ad2f230575f7" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">At December 31, 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 605</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current portion of deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">106,465</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,871</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">125,336</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term portion of deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,708</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">35,318</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,026</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accumulated deficit</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,187,398</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(53,636</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,241,034</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;&#160;&#160;Noncontrolling interest in Akcea Therapeutics, Inc.</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">87,847</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3,580</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,267</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total stockholders&#8217; equity</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">418,719</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(53,439</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">365,280</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Consolidated Statements of Operations</font></div>
    <div><br>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2017</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 605</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112,540</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">-</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112,540</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Licensing and other royalty revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,519</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2,045</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,474</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total commercial revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">122,059</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2,045</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120,014</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research and development revenue under collaborative agreements</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">385,607</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,558</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">394,165</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">507,666</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,513</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">514,179</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income from operations</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24,534</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,513</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">31,047</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(17,296</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,513</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(10,783</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,970</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,316</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">346</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income per share, basic and diluted</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.08</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.07</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.15</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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    <table cellspacing="0" cellpadding="0" id="z7860dc98a8e74b4299f05b8a2975b21a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2016</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Revenue:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">883</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">883</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Licensing and other royalty revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">19,839</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,045</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,884</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total commercial revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">20,722</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,045</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,767</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research and development revenue under collaborative agreements</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">325,898</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24,111</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">350,009</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">346,620</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">372,776</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,156</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(20,160</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(86,556</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(86,556</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
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          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,156</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) per share, basic and diluted</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.72</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.22</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.50</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Consolidated Statements of Cash Flows</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 605</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(17,296</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,513</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(10,783</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -27.15pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">36,695</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(6,513</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,182</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents at beginning of year</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,685</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,685</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents at end of year</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">129,630</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">129,630</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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    <table cellspacing="0" cellpadding="0" id="ze9c1c235f929441b864d9e2fc43f9be3" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
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          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(86,556</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(60,400</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -27.15pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(59,150</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(26,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(85,306</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents at beginning of year</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">128,797</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">128,797</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash and cash equivalents at end of year</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,685</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">84,685</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:06add39f-ca6f-4863-8fb3-28d5566ba4a2">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under Topic 606, compared to Topic 605, our total revenue increased $6.5 million for <font style="font-size: 10pt; font-family: 'Times
        New Roman', Times, serif;">2017</font> and $26.2 million for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2016</font>. The change in our revenue was primarily due to:</div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z80d3e2378bdd410699ebdf21c591797b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>A change in how we recognize milestone payments:</u></font> Topic 606 requires
                    us to amortize more of the milestone payments we achieve, rather than recognizing the milestone payments in full in the period in which we achieved the milestone event as we did under Topic 605. This change resulted in an increase in
                    R&amp;D revenue recognized for 2017 and 2016 of $23.7 million and $24.1 million, respectively.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7833d8385aec4724a5166c5362d39bbd" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>A change in how we calculate revenue for payments we are recognizing into
                        revenue over time:</u></font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> Under Topic 605, we amortized payments into revenue evenly over the period of our obligations. When we made a change to our
                      estimated completion period, we recognized that change on a prospective basis. Under Topic 606, we are required to use an input method to determine the amount we amortize each reporting period. Each period we review our &#8220;inputs&#8221; such
                      as our level of effort expended, including the time we estimate it will take us to complete the activities or costs incurred, relative to the total expected inputs to satisfy the performance obligation. For certain collaborations,
                      such as Bayer and Novartis, the input method resulted in a change to the revenue we had previously recognized using a straight-line amortization method.</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times,
                      serif;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">This change resulted in a decrease in our R&amp;D revenue of $15.1 million for 2017. This change did not result in an impact to our 2016
                      R&amp;D revenue.</font></font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our updated revenue recognition policy reflecting Topic 606 is as follows:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Our Revenue Sources</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting
        the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing
        revenue, we include the amounts in deferred revenue on our consolidated balance sheet.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as
        commercial revenue future sales milestone payments and royalties we earn under our partnerships.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Commercial Revenue: TEGSEDI Product Sales, net</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We began adding product sales from TEGSEDI to
          our commercial revenue in the fourth quarter of 2018. </font>In the U.S., TEGSEDI is distributed through an exclusive distribution agreement with a third-party logistics company, or 3PL, that takes title to TEGSEDI. The 3PL is our sole customer
        in the U.S. The 3PL then distributes TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distribute TEGSEDI to health care providers and patients. In Germany, TEGSEDI is distributed
        through a non-exclusive distribution model with a 3PL that takes title to TEGSEDI. The 3PL is our sole customer in Germany. The 3PL in Germany then distributes TEGSEDI to hospitals and pharmacies.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-12</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Research and development revenue under collaborative agreements</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis.
        Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;D, services, and manufacturing services.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our collaboration agreements are detailed in Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements.</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>Under each collaboration note we discuss our specific
        revenue recognition conclusions, including our significant performance obligations under each collaboration.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Steps to Recognize Revenue</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use a five step process to determine the amount of revenue we should recognize and when we should recognize it. The
        five step process is as follows:</font></div>
    <div><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zc7b1364f05eb40e8864e43d543229bc3" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">1.</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Identify the contract</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met
        each of the following criteria:</font></div>
    <div><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z93fa338aa3204df9aa0289ac555ed36c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We and our partner approved the contract and we are both committed to perform our obligations;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zced333b81a9e4e0b9637e667d5e79725" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have identified our rights, our partner&#8217;s rights and the payment terms;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zbb9bf382b08045de922a7cb3208e98a6" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a
                    result of the contract; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z6a7916fc35a043eba1b42243593ad0f6" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe collectability is probable.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="margin-bottom: 10pt;"><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zfa30a56941df44858d7c1a26de8078a4" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">2.</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Identify the performance obligations</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We next identify the distinct goods and services we are required to provide under the contract. Accounting rules refer to
        these as our performance obligations. We typically have only one performance obligation at the inception of a contract, which is to perform R&amp;D services.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Often times we enter into a collaboration agreement in which we provide our partner with an option to license a medicine
        in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We evaluate whether these options are material rights at the
        inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the options we grant to license a medicine in the future or to provide
        additional goods and services as requested by our partner are not material rights. These items are contingent upon future events that may not occur. When a partner exercises its option to license a medicine or requests additional goods or services,
        then we identify a new performance obligation for that item.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the
        license and we do not have any additional performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zdd5c893f26f04a159a7cebe9ec84292f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">3.</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Determine the transaction price</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the
        collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone
        payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because
        the payments are not probable. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most
        likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone
        payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the
        majority of our milestone payments are contingent upon events that are not within our control and are usually based on scientific progress. For example, in the first quarter of 2019, we earned a $35 million milestone payment from Roche when it
        dosed the first patient in the Phase 3 study of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.&#160; At December 31, 2018, we determined it was not probable that we could earn this milestone payment.&#160;As such, we did not recognize any revenue associated with it in 2018.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160; &#160;</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zb9c0b747c142455dbef7c367e1c59bc4" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">4.</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Allocate the transaction price</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction
        price to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the
        transaction price to each performance obligation based on the relative stand-alone selling price.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-13</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price
        for collaborations in which we deliver a license at the start of an agreement. We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the
        amount of income, net of taxes, for the license. We then discount the projected income to present value. The significant inputs we use to determine the projected income of a license could include:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z89a4cb07ebf14fbf9ffcd5ea0933f5ab" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Estimated future product sales;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z52675dcd97714caa8a174e62a058cb50" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Estimated royalties on future product sales;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z54019794e81f41aa97c227e1fbfc96ad" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Contractual milestone payments;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z98b30a1e1a3a498a8f757e49ea9ad628" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expenses we expect to incur;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z3972d2c7bee74c51a512aba24b821799" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income taxes; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z8997db417f6b4612a46ac47c6d0601e7" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A discount rate.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We typically estimate the selling price of R&amp;D services by using our internal estimates of the cost to perform the
        specific services. The significant inputs we use to determine the selling price of our R&amp;D services include:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zfea5a5124d0d4a11a716b5186d509afd" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The number of internal hours we estimate we will spend performing these services;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z3b9e6578ebec497c8baf164bd75bd8a9" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of work we will perform;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z95efefad576044ff9be48a5fcf359a53" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of work that we will contract with third parties to perform; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
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              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of API we will use.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For purposes of determining the stand-alone selling price of the R&amp;D services we perform and the API we will deliver,
        accounting guidance requires us to include a markup for a reasonable profit margin.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone
        selling prices.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z6bef545f96614b2f8ea1c23a150f968a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">5.</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Recognize revenue</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are
        executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;D services. We recognize revenue at a point in time when our partner receives full use
        of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For R&amp;D services that we recognize over time, we measure our progress using an input method. The input methods we use
        are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a
        given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach
        requires us to make numerous estimates and use significant judgement. If our estimates or judgements <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">change over the course of the collaboration, they may affect the
          timing and amount of revenue that we recognize in the current and future periods.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following are examples of when we typically recognize revenue based on the types of payments we receive.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Commercial Revenue:
            SPINRAZA royalties and Licensing and other royalty revenue</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize royalty revenue in the period in
          which the counterparty sells the related product, which in certain cases may require us to estimate our royalty revenue. </font>We recognize royalties from SPINRAZA sales in the period Biogen records the sale of SPINRAZA. Our accounting for
        SPINRAZA royalties did not change as a result of adopting Topic 606.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Commercial Revenue:
            TEGSEDI Product Sales, net</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize TEGSEDI product sales in the
          period </font>when our customer obtains control of TEGSEDI, which occurs at a point in time upon transfer of title to the customer. We classify payments to customers or other parties in the distribution channel for services that are distinct and
        priced at fair value as selling, general and administrative expenses in our consolidated statements of operations. Otherwise payments to customers or other parties in the distribution channel that do not meet those criteria are classified as a
        reduction of revenue, as discussed further below. We exclude from revenues, taxes collected from customers relating to product sales and remitted to governmental authorities.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Reserves for TEGSEDI Product Sales</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We record TEGSEDI product sales at our net sales price, or transaction price. We include in our transaction price
        estimated reserves for discounts, returns, chargebacks, rebates, co-pay assistance and other allowances that we offer within contracts between us and our customers, wholesalers, health care providers and other indirect customers. We estimate our
        reserves using the amounts we have earned or what we can claim on the associated sales. We classify our reserves as reductions of accounts receivable when the amount is payable to our customer or a current liability when the amount is payable to a
        party other than our customer in our consolidated balance sheet. In certain cases, our estimates include a range of possible outcomes that are probability-weighted for relevant factors such as our historical experience, current contractual and
        statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflect our best estimates under the terms of our respective contracts. When calculating our
        reserves and related product sales, we only recognize amounts to the extent that we consider it probable that we would not have to reverse in a future period a significant amount of the cumulative sales we previously recognized. The actual amounts
        we receive may ultimately differ from our reserve estimates. If actual amounts in the future vary from our estimates, we will adjust these estimates, which would affect our net TEGSEDI product sales in the respective period.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-14</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following are the components of variable consideration related to TEGSEDI product sales:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Chargebacks: </font>In
        the U.S., we estimate obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer
        charges us for the difference between what it pays for the product and the selling price to the qualified healthcare providers. We record reserves for these chargebacks related to TEGSEDI product sales to our U.S. customer during the reporting
        period. We also estimate the amount of product remaining in the distribution channel inventory at the end of the reporting period that we expect our customer to sell to wholesalers in future periods.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Government rebates</font>:
        We are subject to discount obligations under government programs, including Medicaid programs and Medicare in the U.S. We estimate Medicaid and Medicare rebates based on a range of possible outcomes that are probability-weighted for the estimated
        payer mix. We record these reserves as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales in the same period we recognize the related sale. For Medicare rebates, we also estimate
        the number of patients in the prescription drug coverage gap for whom we will owe an additional liability under the Medicare Part D program. On a quarterly basis, we update our estimates and record any adjustments in the period that we identify the
        adjustments. In Germany, pharmaceutical companies must grant a specified rebate percentage to the German government. We include this rebate in the same period we recognize the related TEGSEDI product sales, resulting in a reduction of product
        sales.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Trade discounts and
          allowances: </font>We provide customary invoice discounts on TEGSEDI product sales to our U.S. customer for prompt payment. We record this discount as a reduction of TEGSEDI product sales in the period in which we recognize the related product
        revenue. In addition, we receive and pay for various distribution services from our U.S. customer and wholesalers in our U.S. distribution channel. For services we receive that are either not distinct from the sale of TEGSEDI or for which we cannot
        reasonably estimate the fair value, we classify such fees as a reduction of TEGSEDI product sales.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Product Returns: </font></font>Our




      U.S. customer has return rights and the wholesalers have limited return rights primarily related to the expiration date of the TEGSEDI product. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We estimate the amount of
        TEGSEDI product sales that our customer may return. We record our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the
        related sale. Based on our distribution model for TEGSEDI, contractual inventory limits with our customer and wholesalers and the price of TEGSEDI, we believe we will have minimal returns. Our customer in Germany only takes title to the product
        once it receives an order from a hospital or pharmacy and therefore does not maintain any inventory of TEGSEDI, as such we do not estimate returns in Germany.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Other incentives: </font>In





        the U.S., we estimate reserves for other incentives including co-payment assistance we provide to patients with commercial insurance who have coverage and reside in states that allow co-payment assistance. We record a reserve for the amount we
        estimate we will pay for co-payment assistance. We base our reserve on the number of estimated claims and our estimate of the cost per claim related to TEGSEDI product sales that we have recognized as revenue. We record our other incentive reserve
        estimates as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-15</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Research and development
            revenue under collaboration agreements:</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Upfront Payments</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">When we enter into a collaboration agreement with an upfront payment, we typically record the entire upfront payment as
        deferred revenue if our only performance obligation is for R&amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&amp;D services. For example, under our new <font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">collaboration agreement with Roche to</font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> develop IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;for the treatment of complement-mediated diseases</font>, we received a $75 million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our
        single performance obligation, R&amp;D services. We are amortizing the $75 million upfront payment using an input method over the estimated period of time we are providing R&amp;D services. Refer to <font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;">Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font>, for further discussion. Under Topic
        605, we amortized upfront payments evenly over the period of our obligation.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Milestone Payments</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are required to include additional consideration in the transaction price when it is probable. We typically include
        milestone payments for R&amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because there is considerable uncertainty in the research and development processes that trigger
        these payments under our collaboration agreements. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales based milestone payments in the
        period we achieve the milestone under the sales-based royalty exception allowed under accounting rules.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For
        example, in the third quarter of 2017, we initiated a Phase 1/2a clinical study of IONIS-MAPT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>in patients with mild Alzheimer&#8217;s disease. We earned a $10 million milestone payment from Biogen related to the initiation of this study.
        Under Topic 606, we added this payment to the transaction price and allocated it to our R&amp;D services performance obligation. We are recognizing revenue from this milestone payment over our estimated period of performance. Under Topic 605, this
        milestone payment was recognized in full in the third quarter of 2017, which was the period in which we achieved the milestone event.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Conversely, we recognize in full those milestone payments that we earn based on our partners&#8217; activities when our partner
        achieves the milestone event. For example, in the third quarter of 2018, we recognized a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of IONIS-AZ4-2.5-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. <font style="font-size: 10pt; font-family: 'Times
          New Roman', Times, serif;">We concluded that the milestone payment was not related to our R&amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any
          performance obligations related to this milestone payment. </font>Our revenue recognition of milestone payments we earn based on our partners&#8217; activities did not change as a result of adopting Topic 606.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>License Fees</u></font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We generally recognize as revenue the total
          amount we determine to be the stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the
          license after delivery. </font>For example, in the fourth quarter of 2018, we earned a $35 million license fee when Biogen licensed IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> from us. Our recognition of license fees did not change as a result of adopting Topic
        606.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Amendments to Agreements</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items
        to determine the accounting for the amendment:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="ze7c2cd43f78b4ce6b2028900e4607c7d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z233ff4e9a2c841cfb067ed317805b840" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If the goods and/or services are at a stand-alone selling price.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original
        agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and at their stand-alone selling price, we then assess whether the remaining goods or
        services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from
        the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated
        revenue as a cumulative adjustment.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-16</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, in May 2015, we entered into an
          exclusive license agreement with Bayer to develop and commercialize IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for the prevention of thrombosis. As part of the agreement, Bayer paid
          us a $100 million upfront payment. At the onset of the agreement, we were responsible for completing a Phase 2 study of IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in people with
          end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif;"> and to initiate development of IONIS-FXI-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also
          eligible to receive milestone payments and tiered royalties on gross margins of IONIS-FXI</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and IONIS-FXI-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of IONIS-FXI-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, to provide R&amp;D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. </font>Refer to <font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font>, for further
        discussion <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">of our accounting treatment for our Bayer collaboration. </font>Our allocation of the consideration we received for the Bayer amendment did not change as a
        result of adopting Topic 606. However, the method in which we are recognizing revenue related to our R&amp;D services performance obligation did change. We are amortizing revenue related to our R&amp;D services performance obligation using the
        input method under Topic 606.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Multiple Agreements</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such
        agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the
        agreements:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zc8ff7f1e13be4a2a97dab662042d0572" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the agreements were negotiated together with a single objective;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zb9d4b335b00d45888690619be061f753" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z1f5c0311ec1b4354bbdd053a3b383569" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the goods and/or services promised under the agreements are a single performance obligation.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that
        accounting guidance requires us to account for them as a combined arrangement.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: a new
        strategic neurology collaboration agreement and a stock purchase agreement, or SPA. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluated the Biogen agreements to determine whether we should treat the agreements
          separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a
          combined basis. Refer to Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font><font style="font-size: 10pt; font-family: 'Times
          New Roman', Times, serif;"> for further discussion of the accounting treatment for the 2018 strategic neurology collaboration with Biogen.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Contracts Receivable</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our contracts receivable balance represents
          the amounts we have billed our partners for goods we have delivered or services we have performed that are due to us unconditionally. When we bill our partners with payment terms based on the passage of time, we consider the contract receivable
          to be unconditional. We typically receive payment within one quarter of billing our partner</font>. Our contracts receivable balance as of December 31, 2017 did not change when we adopted Topic 606.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Unbilled SPINRAZA Royalties</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our unbilled SPINRAZA royalties represent our
          right to receive consideration from Biogen in advance of when we are eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet. </font>Our unbilled SPINRAZA
        royalties as of December 31, 2017 did not change when we adopted Topic 606.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Deferred Revenue</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are often entitled to bill our customers
          and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.</font> During the years
        ended December 31, 2018 and 2017, we recognized $105.3 million and $95.1 million of revenue from amounts that were in our beginning deferred revenue balances for those periods, respectively. Refer to our revenue recognition policy above detailing
        how we recognize revenue for further discussion.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:5a507368-c5eb-4a61-bf88-639eccfa5d72">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the adjustments we were required to make to our deferred revenue amounts to adopt Topic 606 (in
      thousands):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z149f5040277d461a934b98cab663508a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">At December 31, 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 605</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current portion of deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">106,465</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,871</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">125,336</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term portion of deferred contract revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,708</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">35,318</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,026</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total deferred revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">179,173</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">54,189</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">233,362</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:9218232c-d0a0-49c4-9b48-92945bd37eec">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-17</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our deferred revenue balance increased $54.2 million at December 31, 2017 under Topic 606, compared to Topic 605. The increase was
      primarily related to the change in the accounting for certain milestone payments and the way in which we amortize payments. Under Topic 605, we previously recognized the majority of the milestone payments we earned in the period we achieved the
      milestone event, which did not impact our deferred revenue balance. Under Topic 606 we are now amortizing more milestone payments over the period of our performance obligation, which adds to our deferred revenue balance. Additionally, under Topic 605
      we amortized payments evenly over the period of our obligation. Under Topic 606, we are required to use an input method to determine the amount we amortize each reporting period. The increase in deferred revenue relates to agreements with the
      following partners:</div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="za8b0e10ad8c64cfcbd573d8fc694a8a7" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$24.2 million from Biogen;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z11bc1812cd8f4950a44b9d6ea17dcf02" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$15.9 million from AstraZeneca;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z8bddbdb64a8040b58f8a0258d0b4c174" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$11.8 million from Novartis; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zaa951bb65ab3412089c0227918d06b8e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$ 2.3 million from other partners.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:9adc39e6-3ac6-4446-9fc7-a7637d58d3f5">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cost of Products Sold</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We obtained the first regulatory approval for TEGSEDI in July 2018, as a result we began recognizing cost of products sold
        expenses related to TEGSEDI. Our cost of products sold includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the manufacturing and distribution of TEGSEDI. We also may include certain period
        costs related to manufacturing services and inventory adjustments in cost of products sold. Prior to obtaining regulatory approval, we expensed a significant portion of the costs we incurred to produce the TEGSEDI supply we are using in the
        commercial launch as research and development expense.&#160; <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We previously recognized $0.1 million of costs to produce TEGSEDI related to the TEGSEDI commercial revenue we
          recognized in 2018.</font></font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:2f10790e-5bce-41b1-9327-31db4eeea84c">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Research, Development and Patent Expenses</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:974e341c-9a7c-4efd-bb94-6f39c13afbb1">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our research and development expenses include wages, benefits, facilities, supplies, external services, clinical trial and manufacturing
      costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development services prior to the services being
      rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2018, 2017 and 2016, research and development expenses were $411.9 million,
      $372.5 million and $340.4 million, respectively. A portion of the costs included in research and development expenses are costs associated with our partner agreements. For the years ended December 31, 2018, 2017 and 2016, research and development
      costs of approximately $58.7 million, $59.5 million and $187.1 million, respectively, were related to our partner agreements.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:5b1577ff-c2a0-4ddf-bffe-d573c4703b95">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining patents. We amortize patent costs
      over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was 10.1 years at December 31, 2018.</div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The cost of our patents capitalized on our consolidated balance sheet at December 31, 2018 and 2017 was $32.7 million and
        $30.8 million, respectively. Accumulated amortization related to patents was $8.7 million and $8.8 million at December 31, 2018 and 2017, respectively.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:3f95b4d5-734c-43a3-9adb-7a4584686230">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z4e0b76f764104094a9d6c87caff2c338" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ending December 31,</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Amortization</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(in millions)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2019</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2020</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2021</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.5</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2022</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:8606bcd8-a379-4323-875b-db28046cec4a">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications that have future
      value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2018, 2017 and 2016, patent expenses were $2.6 million, $2.1 million and $3.9 million, respectively, and included
      non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $0.8 million, $0.4 million and $2.3 million, respectively.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:593789a3-bf04-4e2b-9c68-4c1ee89cec08">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-18</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Accrued Liabilities</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:1e7a1e98-391c-42a5-958e-4e8f7386f3e9">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our accrued liabilities consisted of the following (in thousands):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="ze64d99b8c2cc401896f4d70f692c7157" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Clinical expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,125</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">16,347</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -18pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In-licensing expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,298</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">33,790</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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: -18pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other miscellaneous expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13,938</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">16,481</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total accrued liabilities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48,361</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">66,618</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:991632f9-5405-4e65-84bf-b802d6fdeb3a">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Noncontrolling Interest in Akcea Therapeutics, Inc.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Prior to Akcea&#8217;s IPO in July 2017, we owned 100 percent of Akcea. From the closing of Akcea&#8217;s IPO in July 2017 through
        mid-April 2018, we owned approximately 68 percent<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>of Akcea. In the second, third and fourth quarters of 2018, we received additional shares of Akcea&#8217;s stock related
        to our license of TEGSEDI and AKCEA-TTR-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to Akcea, increasing our ownership percentage to approximately 75 percent. We reflected this increase in our ownership percentage in these financial statements as an adjustment to
        noncontrolling interest. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The shares third parties own represent an interest in Akcea&#8217;s equity that is not controlled by us. However, as we continue to maintain overall
          control of Akcea through our voting interest, we reflect the assets, liabilities and results of operations of Akcea in our consolidated financial statements. We reflect the noncontrolling interest attributable to other owners of Akcea&#8217;s common
          stock in a separate line on the statement of operations and a separate line within stockholders&#8217; equity in our consolidated balance sheet. In addition, we record a noncontrolling interest adjustment to account for the stock options Akcea grants,
          which if exercised, will dilute our ownership in Akcea. This adjustment is a reclassification within stockholders&#8217; equity from additional paid-in capital to noncontrolling interest in Akcea equal to the amount of stock-based compensation expense
          Akcea had recognized.</font></font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:9eec5284-a806-438e-ba68-3e569412cc1c">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Concentration of Credit Risk</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents,
        short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial
        institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&#8217;s, Standard&#160;&amp; Poor&#8217;s, or S&amp;P, or Fitch, respectively. We have established guidelines
        relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:b7a900a9-a3ca-4e91-b81b-2e79b35a271e">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cash, Cash Equivalents and Short-Term Investments</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents.
        Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as &#8220;available-for-sale&#8221; and carry them at fair market value based upon prices on the last day of the
        fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments. We use the
        specific identification method to determine the cost of securities sold.</font></div>
    <div><br>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies
          that we received as part of a technology license or partner agreement. At December 31, 2018, we held equity investments in two publicly held companies, ProQR Therapeutics N.V., or ProQR, and Antisense Therapeutics Limited, or ATL. We also held
          equity investments in four privately-held companies, Atlantic Pharmaceuticals Limited, Dynacure SAS, Seventh Sense Biosystems and Suzhou Ribo Life Science Co, Ltd.</font></div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2018, we adopted the amended accounting guidance related to the recognition, measurement, presentation, and
        disclosure of certain financial instruments. The amended guidance requires us to measure and record our equity investments at fair value. Additionally, the amended accounting guidance requires us to recognize the changes in fair value in our
        consolidated statement of operations, instead of through accumulated other comprehensive income. Prior to 2018, we accounted for our equity investments in privately held companies under the cost method of accounting. Under the amended guidance we
        account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer. Our
        adoption of this guidance did not have an impact on our results.</font></div>
    <div><br>
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  </div>
  <div id="TRGRSegment:4ed90b34-7565-434e-bde4-7fc94e6c9713">
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    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We reflect our inventory on our consolidated balance sheet at the lower of cost or market value under the first-in,
        first-out method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials they have alternative future uses. We include in inventory raw material costs for
        medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and, as a result, each raw material
        has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We expense these costs as
        R&amp;D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency.</font></div>
    <div style="text-align: justify;"><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-19</font></div>
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We obtained the first regulatory approval for TEGSEDI in July 2018. At December 31, 2018, our physical inventory for
        TEGSEDI included API that we produced prior to when we obtained regulatory approval and accordingly has no cost basis as we had previously expensed the costs as R&amp;D expenses.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to
        their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in
        development and historical write-offs. We did not record any inventory write-offs for the years ended December 31, 2018, 2017 or 2016. Total inventory was $8.6 million and $10.0 million as of December 31, 2018 and 2017, respectively.</font></div>
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  <div id="TRGRSegment:bb78ad2b-5bb5-49dd-a287-5040d44ced83">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which
      consists of the following (in thousands):</div>
    <div><br>
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    <table cellspacing="0" cellpadding="0" id="zb8c6c542cb86429cb80c12a8dbc059de" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Estimated Useful Lives</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(in years)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2018</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Computer software, laboratory, manufacturing and other equipment</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3 to 10</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">53,496</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">66,558</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Building, building improvements and building systems</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15 to 40</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">97,528</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">92,770</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Land improvements</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div style="text-indent: -9pt; margin-left: 9pt; text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;,Times,serif;">20</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,853</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,853</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Leasehold improvements</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5 to 15</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,981</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">26,748</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Furniture and fixtures</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5 to 10</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,283</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,161</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">179,141</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">195,090</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Less accumulated depreciation</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(61,474</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(87,676</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">117,667</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,493</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">132,160</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">121,907</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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    <div><br>
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  </div>
  <div id="TRGRSegment:3eb47ded-ab90-43f6-a093-7053d69386ee">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.</div>
    <div><br>
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  </div>
  <div id="TRGRSegment:826cd990-7132-41d0-ac01-91932127bb58">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value of Financial Instruments</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable,
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    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:c208a09e-5a9a-408a-abd4-c3f68b602fde">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Long-Lived Assets</div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a
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    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:46a3f5fd-d6a7-4b17-8000-1ea602c9f20b">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Use of Estimates</div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The preparation of consolidated financial statements in conformity with accounting principles generally accepted in the
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    <div><br>
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  <div id="TRGRSegment:b238f801-624a-4dad-bb62-c9e6490ee6f6">
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    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We measure stock-based compensation expense for equity-classified awards, principally related to stock options, restricted
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use the Black-Scholes model as our method of valuing option awards and stock purchase rights under our ESPP. On the
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        stock price volatility over the term of the awards, and actual and projected employee stock option exercise behaviors. Option-pricing models were developed for use in estimating the value of traded options that have no vesting or hedging
        restrictions and are fully transferable. Because our employee stock options have certain characteristics that are significantly different from traded options, and because changes in the subjective assumptions can materially affect the estimated
        value, in management&#8217;s opinion, the existing valuation models may not provide an accurate measure of the fair value of our employee stock options. Although we determine the estimated fair value of employee stock options using an option-pricing
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    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">See Note 4, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Stockholders&#8217;





          Equity,</font> for additional information regarding our stock-based compensation plans.</font></div>
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  <div id="TRGRSegment:aa0d0eb8-e333-4a35-89d5-2d05fa2d99c0">
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  <div id="TRGRSegment:079d8e06-7b63-499f-b9df-7d2aea15a5bd">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated other comprehensive loss is primarily comprised of unrealized gains and losses on investments, net of taxes and adjustments
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    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <table cellspacing="0" cellpadding="0" id="z64ba3b1348424373b8a321f5a2d5a3bf" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Beginning balance accumulated other comprehensive loss</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(31,759</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(30,358</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(13,565</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Unrealized losses on securities, net of tax (1)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(280</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(960</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(17,219</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(374</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">447</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Currency translation adjustment</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">23</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(67</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(21</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net other comprehensive loss for the period</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(257</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,401</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(16,793</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ending balance accumulated other comprehensive loss</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(32,016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(31,759</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(30,358</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>

    </table>
    <div style="text-align: justify;"><font id="TRGRRTFtoHTMLTab" style="display: inline-block; text-indent: 0px; font-size: 1px; width: 522pt;">&#160;</font><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zf08c499815264e58ba9541aad67fe3f9" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A tax benefit of $0.3 million was included in other comprehensive loss for the year ended December 31, 2018. There was no tax benefit or expense for other
                    comprehensive loss for the years ended December 31, 2017 or 2016.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:7d9ac470-ac46-4188-8ba1-b95df5fdfe81">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Convertible Debt</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We account for convertible debt instruments, including our 1 percent and 2&#190; percent notes that may be settled in cash upon
        conversion (including partial cash settlement) by separating the liability and equity components of the instruments in a manner that reflects our nonconvertible debt borrowing rate. We determine the carrying amount of the liability component by
        measuring the fair value of similar debt instruments that do not have the conversion feature. If no similar debt instrument exists, we estimate fair value by using assumptions that market participants would use in pricing a debt instrument,
        including market interest rates, credit standing, yield curves and volatilities. We use accounting estimates and assumptions when we determine the fair value of the debt component. These estimates and assumptions we use are judgmental in nature and
        could have a significant impact on the determination of the debt component, and the associated non-cash interest expense.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We assigned a value to the debt component of our convertible notes equal to the estimated fair value of similar debt
        instruments without the conversion feature, which resulted in us recording our debt at a discount. We are amortizing our debt issuance costs and debt discount over the life of the convertible notes as additional non-cash interest expense utilizing
        the effective interest method. For additional information, see Note 3, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Long-Term Obligations and Commitments</font>.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:7cec1338-485c-4fd8-83f7-429f897e19c0">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Segment Information</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have two operating segments, our Ionis
          Core segment and Akcea Therapeutics, our majority-owned affiliate. Akcea is </font>a biopharmaceutical company focused on developing and commercializing medicines to treat patients with rare and serious diseases<font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">. We provide segment financial information and results for our Ionis Core segment and our Akcea Therapeutics segment based on the segregation of revenues and expenses that our chief decision maker
          reviews to assess operating performance and to make operating decisions. We allocate a portion of Ionis&#8217; development, R&amp;D support and general and administrative expenses to Akcea for work Ionis performs on behalf of Akcea.</font></font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:3a2f59c9-b04a-4a38-8530-3e40e1fa0943">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value Measurements</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers
        include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity
        securities in publicly-held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified
        as available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify the majority of our securities as Level 2. We obtain the fair
        value of our Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service
        provider and comparing that fair value to the fair value based on observable market prices. During 2018 and 2017, there were no transfers between our Level 1 and Level 2 investments. When we recognize transfers between levels of the fair value
        hierarchy, we recognize the transfer on the date the event or change in circumstances that caused the transfer occurs.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-21</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following tables present the major security types we held at December 31, 2018 and 2017 that are regularly measured
        and carried at fair value. At December 31, 2018, our ProQR investment was <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">subject to trading restrictions through the fourth quarter of 2019, as a result we</font>
        included a lack of marketability discount in valuing this investment, which is a Level 3 input. At December 31, 2017, we did not have any financial instruments that we valued using Level 3 inputs. The tables segregate each security type by the
        level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities&#8217; fair value (in thousands):</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:639edfda-5b19-4e5e-ac2d-76221b3a5e5c">
    <table cellspacing="0" cellpadding="0" id="z3198859f76d747a98844061c4716c7f5" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At</div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31, 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quoted Prices in</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Active Markets</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Level 1)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Significant Other</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Observable Inputs</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Level 2)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Significant</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Unobservable Inputs</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Level 3)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash equivalents (1)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">146,281</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">146,281</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Corporate debt securities (2)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,252,960</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,252,960</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by U.S. government agencies (3)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">276,612</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">276,612</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by the U.S. Treasury (4)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">260,154</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">260,154</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by states of the U.S. and political subdivisions of the states (3)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">79,942</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">79,942</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div></div>
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div>
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Investment in ProQR Therapeutics N.V. (5)</font></div>
            </div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: rgb(255, 255, 255); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: rgb(255, 255, 255); border-bottom: 2px solid rgb(0, 0, 0);">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,349</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: rgb(255, 255, 255); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: rgb(255, 255, 255); border-bottom: 2px solid rgb(0, 0, 0);">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: rgb(255, 255, 255); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: rgb(255, 255, 255); border-bottom: 2px solid rgb(0, 0, 0);">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,349</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,017,298</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">406,435</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,609,514</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,349</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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    </table>
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    <table cellspacing="0" cellpadding="0" id="z502ef224291943b388d32bb84842f060" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">At</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31, 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quoted Prices in</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Active Markets</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Level 1)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Significant Other</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Observable Inputs</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Level 2)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cash equivalents (1)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">86,262</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">86,262</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Corporate debt securities (6)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">647,461</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">647,461</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by U.S. government agencies (3)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">136,325</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">136,325</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by the U.S. Treasury (3)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,818</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,818</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by states of the U.S. and political subdivisions of the states (7)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">93,932</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">93,932</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">994,798</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">117,080</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">877,718</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div style="text-align: justify; text-indent: 500.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"></font><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zd0dff1d84e1649abb8fb11d2922b00ec" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Included in cash and cash equivalents on our consolidated balance sheet.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="za1ccf6d4e5ea43f398f793dbe2cdcc60" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$50.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
                    consolidated balance sheet.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z41c6efee65f1480fac168bc19cec8f96" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Included in short-term investments on our consolidated balance sheet.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z3c382d71f9ea4889bd242bf1949a30f8" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$14.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
                    consolidated balance sheet.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zea0d05087d3b4959b7a2ed093dc28a59" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Included in other current assets on our consolidated balance sheet.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="ze6f1468d1ec147dc88b2eafd82a515d9" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(6)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$11.9 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
                    consolidated balance sheet.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z4bd1a9f4068840e78fe2d42d26fe8cf2" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(7)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$3.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our
                    consolidated balance sheet.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:e4bb2092-d4ae-4326-8159-b24533a948f9">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Novartis Future Stock Purchase</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2017, we and Akcea entered into a SPA with Novartis. As part of the SPA, Novartis was required to purchase $50
        million of Akcea&#8217;s common stock at the IPO price or our common stock at a premium if an IPO did not occur by April 2018. Therefore, at the inception of the SPA, we recorded a $5.0 million asset representing the fair value of the potential future
        premium we could have received if Novartis purchased our common stock. We determined the fair value of the future premium by calculating the value based on the stated premium in the SPA and estimating the probability of an Akcea IPO. We also
        included a <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">lack of marketability discount when we determined the fair value of the premium because we would have issued unregistered shares to Novartis if they had
          purchased our common stock. We measured this asset using Level 3 inputs and recorded it in other assets on our consolidated balance sheet. Because Akcea completed its IPO before April 2018, Novartis will not purchase additional shares of Ionis
          stock. Therefore, this asset no longer had any value and we wrote-off the remaining balance to other expenses on our third quarter 2017 consolidated statement of operations.</font></font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:515818d6-1b72-4ede-b394-b8a5bc6a8ac3">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-22</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following is a reconciliation of the potential premium we would have received if Akcea had not completed its IPO, measured at fair
      value on a recurring basis using significant unobservable inputs (Level 3) for 2017 (in thousands):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zb55f990dd8ae4e68a799102c4d2d9238" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31, 2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Beginning balance of Level 3 instruments</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Value of the potential premium we will receive from Novartis at inception of the SPA (January
                2017)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5,035</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Write-off of premium to other expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,035</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ending balance of Level 3 instruments</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:bfd37fbc-8b0c-42d7-a8c5-4f23ea89bfa5">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Income Taxes</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets
        and liabilities for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and
        research and development credit carryforwards. We record a valuation allowance when necessary to reduce deferred tax assets to the amount we expect to realize.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial
        recognition and measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by
        determining if the weight of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate
        and measure the tax benefit as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for
        income taxes. Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust
        these reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact
        the provision for income taxes in the period in which such determination is made.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax
        assets. In assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future
        taxable income. We base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should
        actual amounts differ from our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> We record a valuation allowance to
          reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be realized.&#160;</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For U.S. federal income tax purposes, we are required to file separate U.S. federal income tax returns for Ionis and
        Akcea. We began deconsolidating Akcea for U.S. federal income tax purposes upon Akcea&#8217;s initial public offering. As a result, we are required to assess our Ionis stand-alone and Akcea&#8217;s valuation allowances separately even though we consolidate
        Akcea&#8217;s financial results in our consolidated financial statements. We continue to file combined state tax returns in most jurisdictions. As a result, we continue to assess the state portion of our valuation allowance for those jurisdictions on a
        consolidated basis.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have historically recorded a valuation allowance against all our net deferred tax assets due to cumulative financial
        statement losses. However, in the fourth quarter of 2018, we reversed the valuation allowance previously recorded against our Ionis stand-alone U.S. federal net deferred tax assets, resulting in a one-time non-cash tax benefit of $332.1 million.
        Given our current stand-alone Ionis pre-tax income, and assuming we maintain this current level of Ionis stand-alone pre-tax income, we expect to generate income before taxes in the U.S. in future periods at a level that would result in us fully
        utilizing our U.S. federal net operating loss carryforwards and most of our Research and Development and Orphan Drug tax credit carryforwards over the next three years.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We continue to maintain a full valuation allowance of $234.2 million against all of Akcea&#8217;s net deferred tax assets and
        the net state deferred tax assets of Ionis at December 31, 2018 due to uncertainties related to our ability to realize the tax benefits associated with these assets.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate
        due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings.
        Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment.
        Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our
        foreign subsidiaries.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:a019ae7d-aed1-4d9f-acb7-c2a7e870fee7">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-23</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Impact of Recently Issued Accounting Standards</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2016, the FASB issued amended accounting guidance related to lease accounting, which will require us to record
        all leases with a term longer than one year on our balance sheet. When we record leases on our balance sheet under the new guidance, we will record a liability with a value equal to the present value of payments we will make over the life of the
        lease (lease liability) and an asset representing the underlying leased asset (right of use asset). The new accounting guidance requires us to determine if our leases are operating or financing leases. We will record expense for operating leases on
        a straight-line basis as an operating expense. If we determine a lease is a financing&#160;lease, we will record both interest and amortization expense and generally the expense will be higher in the earlier periods of the lease. We adopted this
        guidance on January 1, 2019 and adjusted our opening balance sheet on that date. We elected the available practical expedients. The most significant impact was the recognition of right of use assets and lease liabilities for our operating leases.
        We are in the process of finalizing the impact of the adoption. The adoption will not have an impact on our consolidated statement of operations or statement of cash flows.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 2016, the FASB issued guidance that changes the measurement of credit losses for most financial assets and certain
        other instruments. If we have credit losses, this updated guidance requires us to record allowances for these instruments under a new expected credit loss model. This model requires us to estimate the expected credit loss of an instrument over its
        lifetime, which represents the portion of the amortized cost basis we do not expect to collect. The new guidance requires us to remeasure our allowance in each reporting period we have credit losses. The new standard is effective for annual and
        interim periods beginning after December 15, 2019. Early adoption is permitted for periods beginning after December 15, 2018. When we adopt the new standard, we will make any adjustments to beginning balances through a cumulative-effect adjustment
        to accumulated deficit on that date. We plan to adopt this guidance on January 1, 2020. We are currently assessing the effects it will have on our consolidated financial statements and disclosures.</font></div>
    <div style="text-align: justify;"><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2018, the FASB issued updated guidance for reclassification of tax effects from accumulated other
        comprehensive income (loss). The updated guidance gives entities an option to reclassify amounts included in accumulated other comprehensive income (loss) that under the Tax Act do not have a way to be relieved, and allows a one-time
        reclassification to retained earnings. The updated guidance is effective for all entities for fiscal years beginning after December 31, 2018, and interim periods within those fiscal years. We have decided not to record the reclassification
        adjustments provided by this guidance.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 2018, the FASB issued updated guidance to simplify the accounting for stock-based compensation expense for
        nonemployees. Specifically, we are now expensing grants to nonemployees in a similar manner as grants to employees. Previously, we had to re-value these grants at each reporting period to reflect the current fair value. Under the amended guidance,
        we value grants to nonemployees when we grant them and we will not adjust their value for future changes. We adopted this guidance in the second quarter of 2018. The updated guidance did not have a material impact to our financial results.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In November 2018, the FASB issued clarifying guidance of the interaction between the collaboration accounting guidance and
        the new revenue recognition guidance we adopted on January 1, 2018 (Topic 606). The clarifying guidance included the following:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="za55d128a4cd2448fa3808abcad92d3ce" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">When a participant is considered a customer in a collaborative arrangement, all of the associated accounting under Topic 606 should be applied;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z27437a83e8734542b121568cca707de9" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Adds &#8220;unit of account&#8221; concept to collaboration accounting guidance to align with Topic 606. This is used to determine if revenue is recognized or if a contra
                    expense is recognized from consideration received under a collaboration; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zc47a119b01d3406aa37a80a82c68372a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Precludes revenue from being recognized under Topic 606 when a transaction with a collaborative partner is determined not be a customer and is not directly
                    related to the sales to third parties.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The updated guidance is effective for public entities for fiscal years beginning after December 15, 2019, and interim
        periods within those fiscal years. Early adoption is permitted. We plan to adopt this guidance on January 1, 2020. We are currently assessing the effects it will have on our consolidated financial statements and disclosures.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:faa79293-7b28-4f6c-b24a-f6ae376e58e6">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2. Investments</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As of December 31, 2018, we had primarily invested our excess cash in debt instruments of the U.S. Treasury, financial
        institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&#8217;s, Standard &amp; Poor&#8217;s, or S&amp;P, or Fitch, respectively. We have established guidelines
        relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:561d3143-caa4-4394-a230-3cc3189fa857">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2018:</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z71f19c73ab3943ecb3a1835bb23ca70d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">One year or less</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">77</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">After one year but within two years</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">20</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">After two years but within three and one half years</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">100</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:513ca5ba-ea9d-40cc-8755-0512a4edb052">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As illustrated above, at December 31, 2018, 97 percent of our available-for-sale securities had a maturity of less than two years.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize
        all of these securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the balance sheet date.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-24</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At December 31, 2018, we had an ownership interest of less than 20 percent <font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;">in four private companies and two public companies with which we conduct business. The privately-held companies are </font>Atlantic Pharmaceuticals Limited, Dynacure SAS, Seventh Sense Biosystems and Suzhou Ribo
        Life Science Co, Ltd.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The publicly traded companies are ATL and ProQR. </font></font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:c09b24b3-bf8f-42fd-a772-387dd42c811e">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following is a summary of our investments (in thousands):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z4009ce55bbbe4f89b33a6738384c4b3b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Cost </font>(1)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Gains</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Losses</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Fair Value</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Available-for-sale securities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Corporate debt securities (2)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">956,879</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,858</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">955,034</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by U.S. government agencies</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">168,839</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(104</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">168,738</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by the U.S. Treasury (2)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">244,640</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(77</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">244,578</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by states of the U.S. and political subdivisions of the states</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">63,572</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(323</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">63,249</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total securities with a maturity of one year or less</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,433,930</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">31</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2,362</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,431,599</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Corporate debt securities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">299,018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">194</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,286</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">297,926</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by U.S. government agencies</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">107,789</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">194</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(109</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">107,874</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by the U.S. Treasury</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15,600</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(24</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15,576</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by states of the U.S. and political subdivisions of the states</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">16,980</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(287</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">16,693</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total securities with a maturity of more than one year</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">439,387</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">388</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,706</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">438,069</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total available-for-sale securities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,873,317</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">419</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4,068</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,869,668</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Equity securities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total equity securities included in other current assets (3)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,212</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">137</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,349</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total available-for-sale and equity securities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,874,529</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">556</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4,068</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,871,017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="za5dc17da55084db7879a04347c08b01f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Gross Unrealized</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Estimated</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31, 2017</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Cost </font>(1)</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Gains</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Losses</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Fair Value</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Available-for-sale securities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Corporate debt securities (2)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">500,599</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(752</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">499,849</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by U.S. government agencies</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">83,926</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(212</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">83,714</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by the U.S. Treasury</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">29,428</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(17</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">29,411</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by states of the U.S. and political subdivisions of the states (2)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">29,240</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(122</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">29,122</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total securities with a maturity of one year or less</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">643,193</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,103</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">642,096</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Corporate debt securities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">148,663</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,059</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">147,612</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by U.S. government agencies</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">52,779</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(168</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">52,611</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by the U.S. Treasury</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,409</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,407</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by states of the U.S. and political subdivisions of the states</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">65,550</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(740</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">64,810</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total securities with a maturity of more than one year</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">268,401</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,969</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">266,440</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total available-for-sale securities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">911,594</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3,072</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">908,536</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zed44c7aca23c48aba17a8a17204b0222" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We hold our available-for-sale securities at amortized cost.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: left;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z1ef2650a460340de831e5983a482f0c9" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2)</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Includes investments classified as cash equivalents on our consolidated balance sheet.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zee4cbf52ae6b4313af872b42e99e7344" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize our equity securities at</font> 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<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> on our consolidated
                      balance sheet.</font></font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:7529249d-3034-4497-96c3-1167880b2876">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investments we consider to be temporarily impaired at December 31, 2018 are as follows (in thousands):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z695dbaa99da0408aaaf83131df9c5b94" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Less than 12 Months of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Temporary Impairment</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">More than 12 Months of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Temporary Impairment</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Total Temporary</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Impairment</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Number of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Investments</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Estimated</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Fair Value</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Unrealized</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Losses</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Estimated</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Fair Value</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Unrealized</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Losses</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Estimated</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Fair Value</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Unrealized</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Losses</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Corporate debt securities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">546</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,000,461</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,936</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">126,357</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,208</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,126,818</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3,144</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 16%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by U.S. government agencies</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">161,312</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(109</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">34,403</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(104</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">195,715</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(213</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by the U.S. Treasury</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">36</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">183,212</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(100</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,413</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">184,625</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(101</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 16%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by states of the U.S. and political subdivisions of the states</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">49</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13,868</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(14</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">62,883</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(596</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">76,751</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(610</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total temporarily impaired securities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">681</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,358,853</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2,159</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">225,056</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,909</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,583,909</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4,068</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
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    </table>
    <div><br>
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  </div>
  <div id="TRGRSegment:75c52466-031d-4ab6-8d3d-e44952b4d4c2">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-25</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We believe that the decline in value of our debt securities is temporary and primarily related to the change in market interest rates
      since purchase. We believe it is more likely than not that we will be able to hold these securities to maturity. Therefore, we anticipate full recovery of our debt securities&#8217; amortized cost basis at maturity.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:cfa2e3ce-a0de-435a-a244-9cedaa548dba">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">3. Long-Term Obligations and Commitments</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:afd99079-a028-4bf9-91c5-38caf6e08e77">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The carrying value of our long-term obligations was as follows (in thousands):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="ze57b228adb0c4e5cbcafa134c2f446ef" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1 percent convertible senior notes</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">568,215</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">533,111</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term mortgage debt</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">59,842</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">59,771</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Principal balance of fixed rate note with Morgan Stanley (1)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,500</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,500</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Leases and other obligations</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,163</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,095</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">646,720</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">607,477</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Less: current portion</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(13,749</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,621</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total Long-Term Obligations</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">632,971</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">605,856</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z084151525a2347719dd4038b203507d0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our $12.5 million fixed rate note with Morgan Stanley is included in our current portion of long-term obligations on our consolidated balance sheet at
                    December 31, 2018.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:28a1aa3a-e989-41df-8cab-ad9ead35e0f5">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Convertible Notes</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In November 2014, we completed a $500 million offering of convertible senior notes, which mature in 2021 and bear interest
        at 1 percent. We raised $487 million of proceeds, net of issuance costs. We used a substantial portion of the net proceeds from the issuance of the 1 percent convertible senior notes to repurchase $140 million in principal of our 2&#190; percent
        convertible senior notes at a price of $441.9 million, including accrued interest. As a result, the new principal balance of the 2&#190; percent notes was $61.2 million.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2016, we issued an additional $185.5 million of 1 percent convertible senior notes in exchange for the
        redemption of $61.1 million of our 2&#190; percent convertible senior notes. As a result of the debt exchange we completed in December 2016, we recorded a $4.0 million non-cash loss on early retirement of debt, reflecting the early retirement of the
        majority of our remaining 2&#190;&#160;percent convertible notes in December 2016.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:ebedcae5-1386-47b7-a4d6-8e7f0f995459">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2018, we had a nominal amount of our 2&#190; percent convertible senior notes outstanding. At December 31, 2018, we had the
      following 1 percent convertible senior notes outstanding (amounts in millions except price per share data):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z387369ce502d499289072f8093870088" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: top; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: top; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">1 Percent</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Convertible Senior Notes</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Outstanding balance</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">685.5</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Original issue date ($500 million of principal)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">November 2014</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additional issue date ($185.5 million of principal)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: top; background-color: #CCEEFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">December 2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Maturity date</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: top; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">November 2021</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Interest rate</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: top; background-color: #CCEEFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1 percent</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Conversion price per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">66.81</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -12.05pt; margin-left: 12.05pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total shares of common stock subject to conversion</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:3a7e179a-18aa-451f-a2ab-439ed1a43028">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest is payable semi-annually in arrears on May 15 and November 15 of each year for the 1 percent notes. The 1 percent notes are
      convertible at the option of the note holders prior to July&#160;1, 2021 only under certain conditions. On or after July&#160;1, 2021, the notes are initially convertible into approximately 10.3 million shares of common stock at a conversion price of
      approximately $66.81 per share. We will 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 1 percent notes prior to maturity, and no sinking fund is provided for them.
      If we undergo a fundamental change, holders may require us to purchase for cash all or any portion of their 1 percent notes at a purchase price equal to 100 percent of the principal amount of the notes to be purchased, plus accrued and unpaid
      interest to, but excluding, the fundamental change purchase date.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:bba8842d-496b-4422-93eb-a9a0902d0d0a">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We account for our convertible notes using an accounting standard that requires us to assign a value to our convertible debt equal to
      the estimated fair value of similar debt instruments without the conversion feature and to record the remaining portion in equity. As a result, we recorded our convertible notes at a discount, which we are amortizing as additional non-cash interest
      expense over the expected life of the respective debt. We determined our nonconvertible debt borrowing rate using a combination of the present value of the debt&#8217;s cash flows and a Black-Scholes valuation model. The following table summarizes the
      nonconvertible borrowing rate, effective interest rate and amortization period of our debt discount for our convertible notes:</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="za0c6ea8296f94f18967e69dde94eaded" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td style="width: 41.98%; vertical-align: bottom;">&#160;</td>
          <td style="width: 27.8%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">1 Percent</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Convertible Senior Notes</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Issued in November 2014</font></div>
          </td>
          <td style="width: 2.91%; vertical-align: top;">&#160;</td>
          <td style="width: 27.32%; vertical-align: bottom; border-bottom: #000000 2px solid;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">1 Percent</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Convertible Senior Notes</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Issued in December 2016</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 41.98%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Nonconvertible debt borrowing rate</font></div>
          </td>
          <td style="width: 27.8%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7.4 percent</font></div>
          </td>
          <td style="width: 2.91%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 27.32%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6.8 percent</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 41.98%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Effective interest rate</font></div>
          </td>
          <td style="width: 27.8%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7.8 percent</font></div>
          </td>
          <td style="width: 2.91%; vertical-align: top; background-color: rgb(255, 255, 255);">&#160;</td>
          <td style="width: 27.32%; vertical-align: bottom; background-color: rgb(255, 255, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7.2 percent</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 41.98%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Amortization period of debt discount</font></div>
          </td>
          <td style="width: 27.8%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7 years</font></div>
          </td>
          <td style="width: 2.91%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 27.32%; vertical-align: bottom; background-color: rgb(204, 238, 255);">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5 years</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:ebf2af43-b871-4b7b-8dec-609a5b63d8a5">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-26</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Interest expense for the years ended December 31, 2018, 2017 and 2016 included $35.2 million, $32.5 million and $25.1 million,
      respectively, of non-cash interest expense related to the amortization of the debt discount and debt issuance costs for our convertible notes.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:87b61031-2a10-4329-b9ee-5d4265250ed0">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes information about the equity and liability components of our outstanding 1 percent convertible notes (in
      thousands). We measured the fair values of the convertible notes outstanding based on quoted market prices, which is a Level 2 measurement:</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z78553c29f23d495fb6a5bfb15f20d1be" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center; text-indent: 16pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Fair value of outstanding notes</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">724,966</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">727,420</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Principal amount of convertible notes outstanding</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">685,450</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">685,450</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Unamortized portion of debt discount</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">110,817</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">144,112</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term debt</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">568,215</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">533,111</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Carrying value of equity component</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">219,011</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">219,011</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:34b58c00-c171-43cb-bfe4-41f75da52e57">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Financing Arrangements</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Line of Credit Arrangement</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 2015, we entered into a five-year revolving line of credit agreement with Morgan Stanley Private Bank, National
        Association, or Morgan Stanley. We amended the credit agreement in February 2016 to increase the amount available for us to borrow. Under the amended credit agreement, we can borrow up to a maximum of $30 million of revolving credit for general
        working capital purposes. Under the credit agreement interest is payable monthly in arrears on the outstanding principal at a borrowing rate based on our option of:</font></div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zc74d39ec24ea4599bee1014632d53f1f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

          <tr>
            <td style="width: 58.5pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(i)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">a floating rate equal to the one-month London Interbank Offered Rate, or LIBOR, in effect plus 1.25 percent per annum;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zea8eacaf253545769ba7120f113ae590" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

          <tr>
            <td style="width: 58.5pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(ii)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">a fixed rate equal to LIBOR plus 1.25 percent for a period of one, two, three, four, six, or twelve months as elected by us; or</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7af1fb9229bc41b585854e9cf274b239" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

          <tr>
            <td style="width: 58.5pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(iii)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">a fixed rate equal to the LIBOR swap rate during the period of the loan.</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additionally, after June 1, 2016, we pay 0.25 percent per annum, payable quarterly in arrears, for any amount unused under
        the credit facility. As of December 31, 2018, we had $12.5 million in outstanding borrowings under the credit facility with a 2.31 percent fixed interest rate and a maturity date of September 2019, which we used to fund our capital equipment needs.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The credit agreement includes customary affirmative and negative covenants and restrictions. We are in compliance with all
        covenants of the credit agreement.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Research and Development and Manufacturing Facilities</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In July 2017, we purchased the building that houses our primary R&amp;D facility for $79.4 million. As a result of the
        purchase, we extinguished the financing liability we had previously recorded on our balance sheet. The difference between the purchase price of the facility and the carrying value of our financing liability at the time of the purchase was $7.7
        million. We recognized this amount as a non-cash loss on extinguishment of financing liability for leased facility in our consolidated results of operations in the third quarter of 2017.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also purchased our manufacturing facility in July 2017 for $14.0 million. We previously accounted for the lease on this
        facility as an operating lease. We capitalized the purchase price of the building as a fixed asset in the third quarter of 2017.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We financed the purchase of our primary R&amp;D facility and our manufacturing facility, with mortgage debt of $51.3
        million and $9.1 million, respectively. Our primary R&amp;D facility mortgage has an interest rate of 3.88 percent. Our manufacturing facility mortgage has an interest rate of 4.20 percent. During the first five years of both mortgages we are only
        required to make interest payments. Both mortgages mature in August 2027.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-27</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Maturity Schedules</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:8d3bc671-613d-4425-ad33-e13ec710c477">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Annual debt and other obligation maturities, including fixed and determinable interest, at December 31, 2018 are as follows (in
      thousands):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zdaa9948cf1e04cc0ab4a152fc786737f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2019</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,067</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2020</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,330</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2021</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">694,774</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2022</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,809</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,494</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Thereafter</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">68,108</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">800,582</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Less: current portion</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,890</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Less: fixed and determinable interest</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(41,837</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Less: unamortized portion of debt discount</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(111,426</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Plus: Deferred rent</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,960</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">639,389</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:2fcff955-f134-442b-a9bf-2d3cb8125ebe">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Operating Leases</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Ionis Leases</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We lease a facility adjacent to our manufacturing facility that has laboratory and office space that we use to support our
        manufacturing facility. We lease this space under a non-cancelable operating lease with an initial term ending in June 2021 and an option to extend the lease for up to two five-year periods.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additionally, we lease office space that we sublease to Akcea. We lease this space under a non-cancelable operating lease
        with an initial term ending in June 2023 and an option to extend the lease for one five-year period. The sublease with Akcea is eliminated in our consolidated financial statements. We also lease office equipment under non-cancelable operating
        leases with terms through January 2021.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Akcea Lease</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">On April 5, 2018, Akcea entered into an operating lease agreement for office space located in Boston, Massachusetts for
        its new corporate headquarters. The lease commencement date was August 15, 2018 and Akcea took occupancy in September 2018. Akcea is leasing this space under a non-cancelable operating lease with an initial term ending after 123 months and an
        option to extend the lease for an additional five-year term. Under the lease agreement, Akcea received a three-month free rent period, which commenced on August 15, 2018, and a tenant improvement allowance up to $3.8 million. Akcea provided the
        lessor with a letter of credit to secure its obligations under the lease in the initial amount of $2.4 million, to be reduced to $1.8 million on the third anniversary of the rent commencement date and to $1.2 million on the fifth anniversary of the
        rent commencement date if Akcea meets certain conditions set forth in the lease at each such time. The letter of credit amount is included in deposits and other assets in our consolidated balance sheet.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:cb7afcc1-e192-4b96-a37d-d45c6d01684f">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Annual future minimum payments under our operating leases as of December 31, 2018 are as follows (in thousands):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zb6979d02d42440328b6e6d4bd614ce1e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Operating</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Leases</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2019</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,129</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2020</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,008</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2021</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,725</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2022</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,539</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,505</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Thereafter</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,862</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total minimum payments</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">25,768</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:0919602e-d449-4a31-befa-8c13e3adde11">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Rent expense was $2.6 million, $1.7 million and $2.0 million for the years ended December 31, 2018, 2017 and 2016. We recognized rent
      expense on a straight line basis over the lease term for the lease on our building adjacent to our manufacturing facility, the office building that Akcea subleases and Akcea&#8217;s office space, which resulted in a deferred rent balance of $5.0 million
      and $0.1 million at December 31, 2018 and 2017, respectively.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:12959640-7448-4795-bfaf-a89b5f5d2392">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-28</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">4. Stockholders</font>&#8217;<font style="font-size: 10pt;
        font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Equity</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Preferred Stock</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are authorized to issue up to 15,000,000 shares of &#8220;blank check&#8221; Preferred Stock. As of December 31, 2018, there were
        no shares of Preferred Stock outstanding. We have designated Series&#160;C Junior Participating Preferred Stock but have no issued or outstanding shares as of December 31, 2018.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Common Stock</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At December 31, 2018 and 2017, we had 300,000,000 shares of common stock authorized, of which 137,928,828 and 124,976,373
        were issued and outstanding, respectively. As of December 31, 2018, total common shares reserved for future issuance were 14,839,373.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">During the years ended December 31, 2018, 2017 and 2016, we issued 1,451,000, 1,709,000 and 1,285,000 shares of common
        stock, respectively, for stock option exercises, vesting of restricted stock units, and ESPP purchases. We received net proceeds from these transactions of $27.9 million, $22.9 million and $13.7 million in 2018, 2017 and 2016, respectively.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Stock Plans</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">1989 Stock Option Plan</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as
        amended, provides for the issuance of non-qualified and incentive stock options for the purchase of up to 20,000,000 shares of common stock to our employees, directors, and consultants. The plan expires in January 2024. The 1989 Plan does not allow
        us to grant stock bonuses or restricted stock awards and prohibits us from repricing any options outstanding under the plan unless our stockholders approve the repricing. Options vest over a four-year period, with 25 percent exercisable at the end
        of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. At December 31, 2018, a total of 848,753 options were outstanding, of which options to purchase 831,656 shares
        were exercisable, and 42,925 shares were available for future grant under the 1989 Plan.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">2011 Equity Incentive Plan</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In March 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that
        provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to our employees, directors, and consultants.&#160;In June 2015 and in May 2017, after receiving
        approval from our stockholders, we amended our 2011 Equity Incentive Plan to increase the total number of shares reserved for issuance. We increased the shares available under our 2011 Equity Incentive Plan from 5,500,000 to 11,000,000 in June 2015
        and from 11,000,000 to 16,000,000 in May 2017. The plan expires in June&#160;2021. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or
        stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate
        awarding only options and restricted stock unit awards to our employees, directors and consultants. Under the 2011 Plan, stock options cannot vest in a period of less than two years and restricted stock unit awards cannot vest in a period of less
        than three years. We have granted restricted stock unit awards to our employees under the 2011 Plan which vest annually over a four-year period. At December 31, 2018, a total of 9,705,441 options were outstanding, of which 4,801,904 were
        exercisable, 1,183,154 restricted stock unit awards were outstanding, and 3,340,351 shares were available for future grant under the 2011 Plan.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a
        change in control. In the absence of such provisions, no such acceleration will occur. The stock options and restricted stock unit awards we issue to our chief executive officer and issued to B. Lynne Parshall in her former role as chief operating
        officer will accelerate upon a change of control, as defined in the 2011 Plan. In addition, we implemented a change of control and severance benefit plan that provides for change of control and severance benefits to our executive officers,
        including our chief executive officer and chief financial officer. If we terminate one of our executive officers or if an executive officer resigns for good reason during the period that begins three months before and ends twelve months following a
        change in control of the company, the impacted executive officers&#8217; stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the termination date.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-29</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Corporate Transactions and Change in Control under 2011 Plan</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more
        of the following actions with respect to outstanding stock awards under the 2011&#160;Plan:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z31dce9e8135f407fb62b4eef0da1ff7b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">arrange for assumption, continuation, or substitution of a stock award by a surviving or acquiring entity (or its parent company);</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zaac5bb134b6c42d8892ad75f209cb225" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">arrange for the assignment of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award to the
                    surviving or acquiring corporation (or its parent company);</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z008b370aa4ba425ab00c6e248ccebe49" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">accelerate the vesting and exercisability of a stock award followed by the termination of the stock award;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z23941f54f306439da152365206de3135" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">arrange for the lapse of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zc0efe753b1514cfa84258126613a39d6" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">cancel or arrange for the cancellation of a stock award, to the extent not vested or not exercised prior to the effective date of the corporate transaction,
                    in exchange for cash consideration, if any, as the Board, in its sole discretion, may consider appropriate; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z01d05f7295db48cd9db399d012531348" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">arrange for the surrender of a stock award in exchange for a payment equal to the excess of (a)&#160;the value of the property the holder of the stock award would
                    have received upon the exercise of the stock award, over (b)&#160;any exercise price payable by such holder in connection with such exercise.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">2002 Non-Employee Directors&#8217; Stock Option Plan</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In September 2001, our Board of Directors adopted, and the stockholders subsequently approved, an amendment and
        restatement of the 1992 Non-Employee Directors&#8217; Stock Option Plan, which provides for the issuance of non-qualified stock options and restricted stock units to our non-employee directors. The name of the resulting plan is the 2002 Non-Employee
        Directors&#8217; Stock Option Plan, or the 2002 Plan. In June 2015, after receiving approval from our stockholders, we amended our 2002 Non-Employee Directors Stock Option Plan to increase the total number of shares reserved for issuance. We increased
        the shares available under our 2002 Non-Employee Directors Stock Option Plan from 1,200,000 to 2,000,000. Options under this plan expire ten years from the date of grant. Options granted become exercisable in four equal annual installments
        beginning one year after the date of grant. At December 31, 2018, a total of 757,750 options were outstanding, of which 437,750 were exercisable, 63,099 restricted stock unit awards were outstanding, and 420,762 shares were available for future
        grant under the 2002 Plan.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Employee Stock Purchase Plan</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 2009, our Board of Directors adopted, and the stockholders subsequently approved, the amendment and restatement of
        the ESPP and we reserved an additional 150,000 shares of common stock for issuance thereunder. In each of the subsequent years, we reserved an additional 150,000 shares of common stock for the ESPP resulting in a total of 3,674,596 shares
        authorized under the plan as of December 31, 2018. The ESPP permits full-time employees to purchase common stock through payroll deductions (which cannot exceed 10 percent of each employee&#8217;s compensation) at the lower of 85 percent of fair market
        value at the beginning of the purchase period or the end of each six-month purchase period. Under the amended and restated ESPP, employees must hold the stock they purchase for a minimum of six months from the date of purchase. During 2018,
        employees purchased and we issued to employees 43,416 shares under the ESPP at a weighted average price of $39.03 per share. At December 31, 2018, there were 774,816 shares available for purchase under the ESPP.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Stock Option Activity</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:fecd4cfa-f3a5-4a43-a572-4b2d594d5e37">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2018 (in thousands,
      except per share and contractual life data):</div>
    <div><br>
    </div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Number</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">of Shares</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Average Exercise</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Price Per Share</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Average</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Remaining</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Contractual Term</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Years)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Aggregate</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Intrinsic</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Value</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Outstanding at December 31, 2017</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,397</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
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          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">44.52</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Granted</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,518</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48.40</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Exercised</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,064</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">17.78</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cancelled/forfeited/expired</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(540</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">52.47</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Outstanding at December 31, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,311</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">47.85</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4.41</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">93,663</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Exercisable at December 31, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,071</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">46.83</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3.22</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">63,756</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:20a708a3-0831-4fe9-97ff-502539c4e59c">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The weighted-average estimated fair values of options granted were $25.49, $25.42 and $26.72 for the years ended December 31, 2018, 2017
      and 2016, respectively. The total intrinsic value of options exercised during the years ended December 31, 2018, 2017 and 2016 were $34.8 million, $49.5 million and $28.0 million, respectively, which we determined as of the date of exercise. The
      amount of cash received from the exercise of stock options was $18.9 million, $21.2 million and $12.6 million for the years ended December 31, 2018, 2017 and 2016, respectively. For the year ended December 31, 2018, the weighted-average fair value of
      options exercised was $50.50. As of December 31, 2018, total unrecognized compensation cost related to non-vested stock-based compensation plans was $118.3 million. We will adjust the total unrecognized compensation cost for future changes in
      estimated forfeitures. We expect to recognize this cost over a weighted average period of 1.2 years.</div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-30</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Restricted Stock Unit Activity</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:609dbd15-8050-43e7-a16c-c4c3591dcc69">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the RSU activity for the year ended December 31, 2018 (in thousands, except per share data):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z094ba6a90c294f7cb609ca324fb4be60" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Number of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Shares</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted Average</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Grant Date Fair</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Value Per Share</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-vested at December 31, 2017</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">863</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">49.55</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Granted</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">789</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">51.06</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Vested</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(324</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50.21</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cancelled/forfeited</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(82</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">51.59</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-vested at December 31, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,246</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50.20</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:b80a3a88-6404-4693-aedc-35f421058474">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2018, 2017 and 2016, the weighted-average grant date fair value of RSUs granted was $51.06, $48.88 and
      $41.79 per RSU, respectively. As of December 31, 2018, total unrecognized compensation cost related to RSUs was $27.9 million. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures. We expect to recognize
      this cost over a weighted average period of 1.4 years.</div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Stock-based Compensation Expense and Valuation Information</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:35998ae5-cacb-4d59-a04c-d0b7b0e31121">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes stock-based compensation expense for the years ended December 31, 2018, 2017 and 2016 (in thousands),
      which was allocated as follows and includes $44.3 million, $17.5 million and $10.1 million of stock-based compensation expense for Akcea employees in 2018, 2017 and 2016, respectively:</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z5f1d18b357bb41b49cc8d26ed3660892" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cost of products sold</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">160</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research, development and patent</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">76,557</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">64,521</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">55,099</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selling, general and administrative</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">54,595</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,454</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">17,009</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">131,312</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">85,975</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,108</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:52a43f01-bd56-4c45-a2f9-8b436602b9c7">
    <div style="text-align: justify; text-indent: -18pt; margin-left: 54pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Determining Fair Value</div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Valuation.</font> We
        measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, and stock purchase rights under the ESPP at the grant date, based on the estimated fair value of the award and we recognize the
        expense over the employee&#8217;s requisite service period. We value RSUs based on the market price of our common stock on the date of grant.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our
        ESPP. The expected term of stock options granted represents the period of time that we expect them to be outstanding. We estimate the expected term of options granted based on actual and projected exercise patterns. We recognize compensation
        expense for stock options granted, RSUs, 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.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:6c25f84b-b6c7-4156-9d6d-8b9228b08bd7">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2018, 2017 and 2016, we used the following weighted-average assumptions in our Black-Scholes
      calculations:</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Employee Stock Options:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z72cee88f250245e7864ca374c80a23f5" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Risk-free interest rate</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.5</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dividend yield</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Volatility</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">63.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">65.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">58.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expected life</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4.6 years</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4.5 years</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4.5 years</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Board of Director Stock Options:</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z93de28b672614f1bb13ec9b4dee47c82" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Risk-free interest rate</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dividend yield</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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        <tr>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expected life</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Risk-free interest rate</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.8</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.8</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.4</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dividend yield</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Volatility</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">47.3</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">59.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">86.4</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expected life</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6 months</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6 months</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6 months</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
        </tr>

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  <div id="TRGRSegment:ff19aa2f-1004-4ce5-b22a-6575b3c905b4">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Risk-Free Interest Rate.</font> We base
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    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Dividend Yield.</font> We
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    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Volatility.</font> We use
        an average of the historical stock price volatility of our stock for the Black-Scholes model. We computed the historical stock volatility based on the expected term of the awards.</font></div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Expected Life. </font>The





        expected term of stock options we have granted represents the period of time that we expect them to be outstanding. We estimated the expected term of options we have granted based on actual and projected exercise patterns.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Forfeitures.</font> We
        reduce stock-based compensation expense for estimated forfeitures. We estimate forfeitures at the time of grant and revise, if necessary, in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on
        historical experience. Our historical forfeiture estimates have not been materially different from our actual forfeitures.</font></div>
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  <div id="TRGRSegment:496b8603-7f3c-47c2-9faa-c9f43015f39a">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition to our stock plans, Akcea has its own stock plan under which it grants options and RSUs and under which it derives its
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    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Employee Stock Options:</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Risk-free interest rate</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dividend yield</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Volatility</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expected life</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6.08 years</font></div>
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    <div><br>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Board of Director Stock Options:</font></div>
    <div><br>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Risk-free interest rate</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.9</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.9</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Dividend yield</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Volatility</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">78.2</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">79.4</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">79.6</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expected life</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6.42 years</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6.25 years</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6.08 years</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
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  <div id="TRGRSegment:8add95cc-15ae-42af-8048-0d33d0e61a51">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following summarizes the Black-Scholes input methodology for Akcea options that differs from the methodology we use for Ionis
      options:</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Volatility.</font> Since
        Akcea does not have sufficient history to estimate the volatility of its common stock, Akcea calculates its expected volatility based on a blend of its historical volatility and reported data from selected publicly traded peer companies for which
        historical information is available. Akcea plans to continue to use this blend to calculate its volatility until the historical volatility of its common stock is sufficient to measure expected volatility for future option grants.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Expected Life. </font>Since





        Akcea does not have sufficient historical information, it uses the simplified method for estimating its expected term. Under the simplified method Akcea calculates its expected term as the average time-to-vesting and the contractual life of the
        options. As Akcea gains additional historical information, it will transition to calculating its expected term based on its exercise patterns.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:c3008836-c349-4a2a-a25e-2d078285943d">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-32</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">5. Income Taxes</div>
    <div><br>
    </div>
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  <div id="TRGRSegment:e5bc9032-408d-4405-b74b-80d92075e1b3">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss before income tax (benefit) expense is comprised of (in thousands):</div>
    <div><br>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(69,576</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,289</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(57,466</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Foreign</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(6,580</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(11,474</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Loss before income tax (benefit) expense</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(76,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(16,763</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(57,466</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
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    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:f52275ef-f929-4255-8c38-dbe15be9fe7c">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our income tax (benefit) expense was as follows (in thousands):</div>
    <div><br>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Federal</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">438</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(7,460</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,067</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">State</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,442</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,246</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,867</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Foreign</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">374</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">234</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total current income tax (benefit) expense</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(630</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,980</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Federal</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(290,511</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">State</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total deferred income tax (benefit) expense</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(290,511</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total income tax (benefit) expense</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(291,141</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,980</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,934</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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  </div>
  <div id="TRGRSegment:c50842e6-fd5e-4441-9bdd-757a2aac460c">
    <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The reconciliation between our effective tax rate on loss from continuing operations and the statutory U.S. tax rate is as follows (in
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    <table cellspacing="0" cellpadding="0" id="z43c1545cdb564ab8a33d8f27c7337ff4" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="22" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Pre-tax loss</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(76,156</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(16,763</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(57,466</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#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 style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Statutory rate</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,867</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">35.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(20,113</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">35.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">State income tax net of federal benefit</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2,202</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.9</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">820</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">95</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.2</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Foreign</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,735</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2.3</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,299</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(25.6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net change in valuation allowance</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(277,924</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">364.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(86,296</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">514.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">46,402</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(80.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net operating loss expiration</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,864</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(11.6</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,987</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(23.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI licensing gain</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">59,583</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(78.2</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Tax credits</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(73,362</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">96.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(32,769</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">195.5</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(26,954</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">46.9</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred tax true-up</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,947</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(13.1</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,848</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(28.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,591</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4.5</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Tax rate change</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,808</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.4</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">114,832</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(685.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Non-deductible compensation</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,154</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4.1</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,575</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(9.4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">825</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1.4</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other non-deductible items</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(569</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.7</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(15.2</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">324</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea deconsolidation adjustment at IPO</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">469</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Stock-based compensation</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4,199</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5.5</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(14,337</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">85.5</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,633</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(89</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.5</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(236</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 28%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Effective rate</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(291,141</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">382.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,980</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">35.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,934</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)%</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:11a53b75-d609-43e5-9808-2efb4bb65a24">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-33</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Significant components of our deferred tax assets and liabilities as of December 31, 2018 and 2017 are as follows (in thousands):</div>
    <div><br>
    </div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div>
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          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
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            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred Tax Assets:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net operating loss carryovers</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">89,717</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">153,575</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D credits</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">313,652</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">240,290</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">27,381</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">54,302</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Stock-based compensation</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">61,027</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">40,090</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Intangible and capital assets</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">49,007</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">672</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,275</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,164</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total deferred tax assets</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">549,059</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">501,093</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred Tax Liabilities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Convertible debt</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(24,018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(32,391</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net deferred tax asset</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">525,041</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">468,702</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Valuation allowance</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(234,245</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(468,702</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total net deferred tax assets and liabilities</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">290,796</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:27341507-4ac6-4a4f-958e-626dce281600">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We have adjusted all prior year tax amounts to reflect the tax impact of our adoption of Topic 606.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate
        due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings.
        Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment.
        Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have historically recorded a valuation allowance against all our net deferred tax assets due to cumulative financial
        statement losses. However, in the fourth quarter of 2018, we reversed the valuation allowance previously recorded against Ionis&#8217; stand-alone U.S. federal net deferred tax assets, resulting in a one-time non-cash tax benefit of $332.1 million. Given
        our current stand-alone Ionis pre-tax income, and assuming we maintain this current level of Ionis stand-alone pre-tax income, we expect to generate income before taxes in the U.S. in future periods at a level that would result in us fully
        utilizing our U.S. federal net operating loss carryforwards and most of our Research and Development and Orphan Drug tax credit carryforwards over the next three years.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We continue to maintain a full valuation allowance of $234.2 million against all of Akcea&#8217;s net deferred tax assets and
        the net state deferred tax assets of Ionis at December 31, 2018 due to uncertainties related to our ability to realize the tax benefits associated with these assets.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our valuation allowance decreased by $234.5 million from December 31, 2017 to December 31, 2018.&#160; The net decrease relates
        primarily to the reversal of the valuation allowance previously recorded against Ionis&#8217; stand-alone U.S. federal net deferred tax assets, offset by current year utilization of a portion of our net operating loss carry forwards.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At December 31, 2018, we had federal and state, primarily California, tax net operating loss carryforwards of $284.6
        million and $808.7 million, respectively. Our federal tax loss carryforwards will begin to expire in 2033, unless we use them before then. Our California loss carryforwards continued to expire in 2018. At December 31, 2018, we also had federal and
        California research and development tax credit carryforwards of $288.9 million and $68.4 million, respectively. Our Federal research and development tax credit carryforwards began to expire in 2018. Our California research and development tax
        credit carryforwards are available indefinitely.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the
        ownership change limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation may result in the expiration of net operating losses and credits before utilization.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">On December 22, 2017, the U.S. government enacted comprehensive tax legislation commonly referred to as the Tax Cuts and
        Jobs Act of 2017, or the Tax Act. The Tax Act made broad and complex changes to the U.S. tax code, including, but not limited to, reducing the U.S. federal corporate income tax rate to 21 percent, imposing a mandatory one-time transition tax on
        certain unrepatriated earnings of foreign subsidiaries and eliminating the corporate alternative minimum tax, or AMT, and changing how existing AMT credits can be realized. We were required to recognize the tax effect of the tax law changes the
        year of enactment. In order to calculate these effects, we were required to determine the transition tax amount, remeasure our U.S. deferred tax assets and liabilities, and consider the impact to our AMT tax credit carryforwards. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For the year ended December 31, 2017, we recorded provisional amounts in accordance with that guidance where it was possible for us to make reasonable estimates of the effects
          of the Tax Act. We evaluated the decrease in our corporate tax rate and recorded a provisional, one-time tax expense of $107.3 million at December 31, 2017. We fully offset our tax effect by a decrease in our valuation allowance which resulted in
          no net tax effect in 2017.</font> During the fourth quarter of 2018, we completed our accounting for all aspects of the Tax Act. We did not identify material changes from our 2017 provisional analysis.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-34</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We analyze filing positions in all U.S. federal, state and foreign jurisdictions where we file income tax returns, and all
        open tax years in these jurisdictions to determine if we have any uncertain tax positions on any of our income tax returns. We recognize the impact of an uncertain tax position on an income tax return at the largest amount that the relevant taxing
        authority is more-likely-than not to sustain upon audit. We do not recognize uncertain income tax positions if they have less than 50 percent likelihood of the applicable tax authority sustaining our position.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:073a7bef-9d87-4492-9296-d729fe00319d">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes our gross unrecognized tax benefits (in thousands):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="ze29ce5459d2f4734a5e9626a7ee62a66" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Beginning balance of unrecognized tax benefits</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">78,014</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">66,999</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">51,257</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Settlement of prior period tax positions</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4,033</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Decrease for prior period tax positions</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,814</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Increase for prior period tax positions</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,520</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,928</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Increase for current period tax positions</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,101</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,495</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,847</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ending balance of unrecognized tax benefits</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">68,301</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">78,014</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">66,999</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:c31c8cc5-42bc-48e8-9a94-e449bbac8eea">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in the balance of unrecognized tax benefits at December&#160;31, 2018, is $55.5 million that could impact our effective tax rate,
      subject to our remaining valuation allowance.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not foresee any material changes to our gross unrecognized tax benefits within the next twelve months.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize interest and/or penalties related to income tax matters in income tax expense. We did not recognize any
        accrued interest and penalties related to gross unrecognized tax benefits during the year ended December 31, 2018.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are subject to taxation in the U.S. and various state and foreign jurisdictions. <font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">Our tax years for 1999 through 2018 are subject to examination by the U.S. federal, state and foreign tax authorities.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our
        foreign subsidiaries as we consider those earnings to be permanently reinvested. It is not practicable for us to calculate the amount of unrecognized deferred tax liabilities associated with these earnings.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are subject to periodic audits by domestic and foreign tax authorities; however, we are not aware of any audits at this
        time. We believe that we have appropriate support for the income tax positions taken on our tax returns and our accruals for tax liabilities are adequate for all open audit years. Our conclusions are based on an assessment of many factors,
        including past experience and interpretations of tax law applied to the facts of each matter.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:4c56c404-6ab0-4090-9b87-24cb254e0093">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">6. Collaborative Arrangements and Licensing Agreements</div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Strategic Partnership</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:4fb6cc6c-c134-4daf-968c-508fe5087d3f">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Biogen</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have several strategic collaborations with
          Biogen focused on using antisense technology to advance the treatment of neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen&#8217;s expertise in developing therapies for neurological
          disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with spinal muscular atrophy, or SMA. In</font> December 2017, we entered into a collaboration with Biogen to identify <font style="background-color:
          #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">new antisense medicines for the treatment of SMA</font>. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additionally, we and Biogen are
          currently developing six other medicines to treat neurodegenerative diseases under these collaborations, including IONIS-SOD1</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for ALS, IONIS-MAPT</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx





        </sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">for Alzheimer&#8217;s disease</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">,</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> IONIS-C9</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">for ALS, and IONIS-BIIB6</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, IONIS-BIIB7</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and IONIS-BIIB8</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> to treat undisclosed neurodegenerative diseases. In addition
          to these medicines, we and Biogen are evaluating numerous additional targets to develop medicines to treat neurological diseases. In April 2018, we entered into a new strategic collaboration for the treatment of neurological diseases with Biogen.
          From inception through December 2018, we have received over $2.0 billion from our Biogen collaborations, including $1 billion we received from Biogen in the second quarter of 2018 for our 2018 strategic neurology collaboration.</font></font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-35</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Spinal Muscular Atrophy Collaborations</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">SPINRAZA</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2012, we entered into a
          collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA. Biogen reported in </font>January 2019 that SPINRAZA was approved in over 40 countries around the world. In February
        2019, SPINRAZA was approved in China. Biogen is responsible for global SPINRAZA commercial activities.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From inception through December 2018, we earned more than $785 million in total revenue under our SPINRAZA collaboration,
        including more than $350 million in revenue from SPINRAZA royalties and more than $435 million in R&amp;D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on any net sales of SPINRAZA. We have exclusively in-licensed
        patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible
        for all further global development, regulatory and commercialization activities and costs for SPINRAZA.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Over the course of our SPINRAZA collaboration, we identified two performance obligations, which were to perform R&amp;D
        services and to deliver the SPINRAZA license to Biogen. As we achieved milestone payments for our R&amp;D services, we included these amounts in our transaction price for our R&amp;D services performance obligation. We recognized revenue for our
        R&amp;D services performance obligation over our period of performance through December 2016. We recognized the $75 million license fee for SPINRAZA as revenue when we delivered the license to Biogen in July 2016 because Biogen had full use of the
        license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also earned additional milestone payments subsequent to delivering the license to Biogen that we recognized in full in
        the period each milestone payment became probable because we did not have a performance obligation related to each milestone payment. For example, we received $90 million of milestone payments for the approval of SPINRAZA in the EU and Japan in
        2017 and recognized the full amounts into revenue in the period Biogen achieved the milestone events.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">New antisense medicines for the treatment of SMA</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2017, we entered into a
          collaboration agreement with Biogen to </font>identify <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">new antisense medicines for the treatment of SMA</font><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;">. </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Biogen will have the option to license therapies arising out of this collaboration
          following the completion of preclinical studies. Upon licensing, Biogen </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">will be responsible for all further global development, regulatory and commercialization
          activities and costs for such therapies</font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. Under the collaboration agreement, we received a&#160;</font>$25 million<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;upfront payment in December 2017. We will receive development and regulatory milestone payments from Biogen if new medicines advance towards
          marketing approval. </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In total over the term of our collaboration, we are eligible to receive up to $1.2 billion in license fees, milestone payments and other
          payments, including up to $80 million for the achievement of development milestones, up to $180 million for the achievement of commercialization milestones and up to $800 million for the achievement of sales milestones. In addition, we are
          eligible to receive tiered royalties </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">from the mid-teens to </font><font style="font-size: 10pt; font-family: 'Times New Roman',
          Times, serif;">mid-20 percent range </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">on net sales.</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">
          We will achieve the next payment of up to $60 million</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">for the license of a medicine under this collaboration. </font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services
        for Biogen. We determined the transaction price to be the $25 million upfront payment we received when we entered into the collaboration. We allocated the transaction price to our single performance obligation. We are recognizing revenue for our
        R&amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We<font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;"> currently estimate we will satisfy our performance obligation in</font> December 2020.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Neurology Collaborations</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">2018 Strategic Neurology</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In April 2018, we and Biogen entered into a
          new strategic collaboration to develop novel antisense medicines for a broad range of neurological diseases and entered into a SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop
          therapies for these diseases for 10 years. We are responsible for the identification of antisense drug candidates based on selected targets</font>.&#160;Biogen is responsible for conducting IND-enabling toxicology studies for the selected target. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Biogen will have the option to license the selected target </font>after it completes the IND-enabling toxicology study. <font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;">If Biogen exercises its option for a medicine, it will assume </font>all <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">further global development, regulatory and commercialization
          responsibilities and costs for that medicine.&#160;</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the second
          quarter of 2018, we received </font>$1 billion from Biogen, comprised of $625 million to purchase our stock at an approximately 25 percent cash premium and $375 million in an upfront payment. <font style="background-color: #FBFBFB; font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">We are eligible to receive up to $270 million in milestone payments for each medicine that achieves marketing approval. </font>In addition, we are eligible to receive tiered royalties <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">up to the 20 percent</font> range <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">on net
          sales.</font> From inception through December 2018, we have received over $1 billion in payments under this collaboration, including $15 million we received in the fourth quarter of 2018 for advancing two targets under this collaboration. We will
        achieve the next payment of $7.5 million if Biogen designates a target<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> under this collaboration. </font></font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-36</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
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    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, </font>we





        identified one performance obligation, which was to perform R&amp;D services for Biogen.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> We determined our transaction price to be $552 million, comprised of $375 million
          from the upfront payment and $177 million for the premium paid by Biogen for its purchase of our common stock.</font> We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of
        marketability discount. We included a lack of marketability discount in our valuation of the premium because Biogen received restricted shares. We allocated the transaction price to our single performance obligation. In the fourth quarter of 2018,
        we received $15 million in milestone payments when we advanced <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">two </font>targets under this collaboration. We added these payments to our transaction price for our
        R&amp;D services performance obligation. We are recognizing revenue for our R&amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy
        our performance obligation. We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently estimate we will satisfy our performance obligation in </font>June 2028.</font></div>
    <div><br>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">2013 Strategic Neurology</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In September&#160;2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology
        to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines
        resulting from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen will have the option to license antisense medicines after Phase 2 proof of concept. In October 2016, we
        expanded our collaboration to include additional research activities we will perform. If Biogen exercises its option for a medicine, it will assume all further global development, regulatory and commercialization responsibilities and costs for that
        medicine. We are currently advancing five medicines, IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, IONIS-C9<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, IONIS-BIIB6<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, IONIS-BIIB7<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-BIIB8<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> under this collaboration. In the fourth quarter of 2018, Biogen
        licensed IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, and as a result Biogen now is responsible for all further global development, regulatory and commercialization activities and costs for IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone
        payments, license fees and royalty payments for all medicines developed through this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug
        discovery and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee and milestone payments per program. The $260 million per program consists of approximately $60 million in development
        milestones, including amounts related to the cost of clinical trials, and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens
        on net sales from any antisense medicines developed under this collaboration. From inception through December 2018, we have received over $210 million in upfront fees, milestone payments and other payments under this collaboration, not including a
        $5 million milestone payment we earned in the fourth quarter of 2018 for Biogen&#8217;s initiation of a Proof of Concept study for IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>which we received in the first quarter of 2019. We will achieve the next payment of up to $10
        million if we advance a program under this collaboration.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of our strategic neurology collaboration, we identified one performance obligation, which was to
        perform R&amp;D services for Biogen. At inception, we determined the transaction price to be the $100 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&amp;D
        services, we include these amounts in our transaction price for our R&amp;D services performance obligation. We are recognizing revenue for our R&amp;D services performance obligation based on our effort to satisfy our performance obligation
        relative to our total effort expected to satisfy our performance obligation<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. </font>We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">
          currently estimate we will satisfy our performance obligation in</font> September 2019. From inception through December <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2018</font>, we have included $145 million in
        total payments in the transaction price for our R&amp;D services performance obligation. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the third quarter of 2018, we earned a $10 million milestone payment when
          Biogen initiated a Phase 1 study of IONIS-C9</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. We concluded that the milestone payment was not related to our R&amp;D services performance obligation.
          Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any performance obligations related to this milestone payment.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We identified a second performance obligation upon Biogen&#8217;s license of IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in the fourth quarter of
        2018 because the license we granted to Biogen is distinct from our other performance obligation. We recognized the $35 million license fee for IONIS-SOD1<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> as revenue at that time because Biogen had full use of the license without any
        continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen. Additionally, in the fourth quarter of 2018 we <font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;">earned a $5 million milestone when Biogen initiated a Proof-of-Concept study for IONIS-SOD1</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. We concluded that the
          milestone payment was not related to our R&amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the fourth quarter of 2018 because we do not have any performance obligations related to this milestone
          payment.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Neurology</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December&#160;2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense
        medicines to up to three targets to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a
        medicine from each of the programs through the completion of the first Phase 2 study for each program. We are currently advancing IONIS-MAPT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for Alzheimer&#8217;s disease under this collaboration. If Biogen exercises its option for a
        medicine, it will assume all further global development, regulatory and commercialization responsibilities and costs for that medicine.&#160;</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of the agreement, we received
          an upfront payment of $30 million. Over the term of the collaboration, we are eligible to receive up to $210 million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. The $210
          million per program consists of up to $10 million in development milestone payments, plus a mark-up on the cost estimate of the Phase 1 and 2 studies and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory
          milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each of the three programs. From inception through December 2018, we have received $58 million in milestone
          payments and upfront fees under this collaboration. We will achieve the next payment of $7.5 </font>million if we continue to advance IONIS-MAPT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-37</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services
        for Biogen. At inception, we determined the transaction price to be the $30 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&amp;D services, we include these
        amounts in our transaction price for our R&amp;D services performance obligation. We are recognizing revenue for our R&amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative
        to our total effort expected to satisfy our performance obligation. We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently estimate we will satisfy our performance obligation in </font>December 2020. From
        inception through December<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> 2018</font>, we have included $40 million in total payments in the transaction price for our R&amp;D services performance obligation.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:ddc7477e-5fe0-4aa9-8de3-170619eaecc5">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Biogen (in millions,
      except percentage amounts):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zfdb178a348774774926cb7e896eb5c90" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties (commercial revenue)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">237.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112.5</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.9</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">137.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">150.6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">248.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total revenue from our relationship with Biogen</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">375.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">263.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">249.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">63</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">51</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">67</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:89c1d6f1-7e4f-4bf6-a2e5-c0bfcf6283c9">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our </font>consolidated balance sheet at <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">December 31, 2018 and 2017 included deferred revenue of $580.9 million and $93.6 million, respectively, related to our relationship with Biogen.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:0e8fa16e-0f4b-4529-be82-234bcbb9dc05">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Research, Development and Commercialization Partners</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:86bffbaf-ff54-43ca-8e30-b51692eb5d82">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">AstraZeneca</div>
    <div style="text-align: justify;"><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Cardiac, Renal and Metabolic Diseases Collaboration</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In July 2015, we and AstraZeneca formed a
          collaboration to discover and develop antisense therapies for treating cardiac, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed three medicines from us: IONIS-AZ4-2.5-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;">, a medicine we designed to treat cardiovascular disease and our first </font>medicine that combines our Generation 2.5 and<font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif;"> LICA technology, IONIS-AZ5-2.5</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, a medicine we designed to </font>treat a genetically associated form of kidney disease and <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS-AZ6-2.5-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, a medicine we designed to </font>inhibit an undisclosed
        target to treat patients with nonalcoholic steatohepatitis, or NASH<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. AstraZeneca is responsible for all further global development, regulatory and commercialization
          activities and costs for each of the medicines it has licensed and any other future medicines AstraZeneca licenses.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of the agreement, we received a $65 million upfront payment. We are eligible to receive license fees and
        milestone payments of up to more than $4 billion as medicines under this collaboration advance, including up to $1.1 billion for the achievement of development milestones and up to $2.9 billion for regulatory milestones. In addition, we are
        eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. From inception through December 2018, we have received over $165 million in
        upfront fees, license fees, milestone payments, and other payments under this collaboration, including a $10 million milestone payment we earned in the third quarter of 2018 when AstraZeneca initiated a Phase 1 trial for IONIS-AZ4-2.5-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.
        We will achieve the next payment of $10 million under this collaboration if we advance a medicine under this collaboration<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services
        for AstraZeneca. We determined the transaction price to be the $65 million upfront payment we received and we allocated it to our single performance obligation. We are recognizing revenue for our R&amp;D services performance obligation as we
        perform services based on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently
          estimate we will satisfy this performance obligation in</font> August 2021. As we achieve milestone payments for our R&amp;D services, we include these amounts in our transaction price for our R&amp;D services performance obligation. From
        inception through December<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> 2018</font>, we have included $90 million in payments in the transaction price for our R&amp;D services performance obligation.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We identified separate performance obligations upon AstraZeneca&#8217;s license of IONIS-AZ5-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and
        IONIS-AZ6-2.5-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in the first quarter of 2018 because the licenses are distinct from our other performance obligation and each other. We recognized each $30 million license fee in the first quarter of 2018 because AstraZeneca had full
        use of the licenses without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the licenses after we delivered them to AstraZeneca.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the third quarter of 2018, we earned a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of
        IONIS-AZ4-2.5-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. We concluded that the milestone payment was not related to our R&amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any
        performance obligations related to this milestone payment.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-38</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Oncology Collaboration</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December&#160;2012, we entered into a
          collaboration agreement with AstraZeneca to discover and develop antisense medicines to treat cancer.&#160;As part of the agreement, we granted AstraZeneca an exclusive license to develop and commercialize </font>danvatirsen (formerly <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS-STAT3-2.5</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">) for the treatment of cancer. AstraZeneca is now responsible
          for all global development, regulatory and commercialization activities for </font>danvatirsen<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. We and AstraZeneca have evaluated </font>danvatirsen<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in people with head and neck cancer, advanced lymphoma and advanced metastatic hepatocellular carcinoma. AstraZeneca is evaluating </font>danvatirsen<font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;"> in combination with durvalumab, AstraZeneca&#8217;s PD-L1 blocking drug, in people with head and neck cancer, metastatic bladder cancer and metastatic non-small cell lung cancer. We and AstraZeneca
          also established an oncology research program. AstraZeneca has the option to license medicines resulting from the program, and if AstraZeneca exercises its option for a medicine, it will be responsible for all further global development,
          regulatory and commercialization activities and costs for such medicine. In the fourth quarter of 2018, we added </font>IONIS-AZ7-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to our preclinical pipeline, a second drug under our oncology collaboration.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of this agreement, we
          received $31 million in upfront payments. We are eligible to receive milestone payments and license fees from AstraZeneca as programs advance in development. If AstraZeneca successfully develops </font>danvatirsen<font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;"> and another medicine under the research program, we could receive license fees and milestone payments of up to more than $450 million, including up to $152 million for the achievement of development
          milestones and up to $275 million for the achievement of regulatory milestones.&#160;In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any medicines resulting from these programs. From inception through
          December 2018, we have received over $125 million in upfront fees, milestone payments, and other payments under this oncology collaboration, including nearly $30 million in milestone payments we achieved when AstraZeneca advanced </font>danvatirsen





        and IONIS-AZ7-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, in the fourth quarter of 2018. We <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">will achieve the next payment of up to $25 million </font><font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;">if we advance a medicine under our cancer research program with AstraZeneca.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified four performance obligations. We determined the transaction price
        to be the $31 million upfront payments we received. We allocated the transaction price based on the estimated stand-alone selling price of each of our performance obligations and recognized the associated revenue over the period of our performance.
        We recognized revenue for three of our obligations over our period of performance, which concluded in March 2014. Our remaining performance obligation was to perform R&amp;D services. We allocated $7.6 million to this performance obligation and
        recognized the associated revenue over the period of our performance, which ended in February 2018. As we achieved milestone payments for our R&amp;D services, we included these amounts in our transaction price for our R&amp;D services performance
        obligation.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the fourth quarter of 2018, we earned a $17.5 million milestone payment and a $10 million milestone payment when
        AstraZeneca advanced two programs under our collaboration. We recognized these milestone payments in full in the fourth quarter because we do not have any performance obligations related to these milestone payments.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:0e90add1-4f86-4b2f-ae4a-d1ccb8b8f72a">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with AstraZeneca (in
      millions, except percentage amounts):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z2cc00cdcb7e54930856d338dd06a7127" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21.6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">41.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">20</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:bded6a27-0834-452b-81b1-1074b0145e3a">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our </font>consolidated balance sheet at <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">December 31, 2018 and 2017 included deferred revenue of $40.1 million and $57.7 million, respectively, related to our relationship with AstraZeneca.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:cd270a88-d37e-44b7-81b1-66e63a91d945">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Bayer</div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
          for the prevention of thrombosis. We were responsible for completing a Phase 2 study of IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in people with end-stage renal disease on hemodialysis. Under the terms of the agreement, we received a $100 million upfront payment in
          the second quarter of 2015. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and to initiate development of IONIS-FXI-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, which Bayer licensed. In conjunction with the decision to advance these
          programs, we received a $75 million payment from Bayer. We are conducting a Phase 2b study evaluating IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in people with end-stage renal disease on hemodialysis to finalize dose selection. Additionally, we are developing
          IONIS-FXI-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> through Phase 1. Following these studies and Bayer&#8217;s decision to further advance these programs, Bayer will be responsible for all global development, regulatory and commercialization activities and costs for both
          medicines.&#160;</font></div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are eligible to receive additional milestone payments as each medicine advances toward the market. In total over the
        term of this collaboration, we are eligible to receive up to $385 million in license fees, milestone payments and other payments, including up to $125 million for the achievement of development milestones and up to $110 million for the achievement
        of commercialization milestones. In addition, we are eligible to receive tiered royalties in the low to high 20 percent range on gross margins of both medicines combined. From inception through December 2018, we have received over $175 million from
        our Bayer collaboration. We will achieve the next payment of $10 million if a program advances under this collaboration.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-39</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified three performance obligations. We determined the transaction
        price to be the $100 million upfront payment we received. We allocated the transaction price based on the relative stand-alone selling prices of each of our performance obligations and recognized the associated revenue as follows:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z0cf5a77cf0834ad7bd617d59e4ad93ca" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognized $91.2 million for the exclusive license of IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>in May 2015 because Bayer <font style="font-size: 10pt; font-family: 'Times
                      New Roman', Times, serif;">had full use of the license without any continuing involvement from us</font>.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z8694d63bbe184f9d9f2d0f99b65a3d51" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognized $4.3 million for the R&amp;D services for IONIS-FXI<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> over the period of our performance, which ended in November 2016.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z6ba8d698ef5749b0a254822ff42576f0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We allocated $4.5 million for API, which we are recognizing into revenue as we deliver the API.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2017, when we amended our collaboration with Bayer, we identified two new performance obligations<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, one for the license of IONIS-FXI-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and one for R&amp;D services</font>. We
        determined the transaction price to be the $75 million payment. We allocated $64.9 million to <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">the license of IONIS-FXI-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;"> based on its estimated stand-alone selling price and recognized the associated revenue upon our delivery of the license in the first quarter of 2017. We allocated $10.1 million to our R&amp;D
          services performance obligation based on an estimated stand-alone selling price. </font>We are recognizing revenue for our R&amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation
        relative to our total effort expected to satisfy our performance obligation. We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently estimate we will satisfy our </font>R&amp;D services <font style="font-size:
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    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:8aa834b9-cdcd-4dc4-9597-9123674bfe0b">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Bayer (in millions,
      except percentage amounts):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z8d3245bf8c1849b7b588c896d2a9f96b" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">67.1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5.4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
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    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:b0ffd7be-377f-4a9f-98ee-7182c10885fa">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our </font>consolidated balance sheet at <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">December 31, 2018 and 2017 included deferred revenue of $4.3 million and $9.3 million, respectively, related to our relationship with Bayer.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:418e83db-b1a8-4b7d-9b33-b75ddb2456c7">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">GSK</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In March&#160;2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop
        new medicines against targets for rare and serious diseases, including infectious diseases and some conditions causing blindness. Under the terms of the agreement, we received upfront payments of $35 million.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">GSK is advancing two medicines targeting hepatitis B virus, or HBV, under our collaboration: IONIS-HBV<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>&#160;and
        IONIS-HBV-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. GSK is currently conducting Phase 2 studies for both of these medicines, which we designed to reduce the production of viral proteins associated with HBV infection. GSK has the exclusive option to license the medicines
        resulting from this alliance at Phase 2 proof-of-concept for a license fee.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under our agreement, if GSK successfully develops these medicines and achieves pre-agreed sales targets, we could receive
        license fees and milestone payments of $262 million, including up to $47.5 million for the achievement of development milestones, up to $120 million for the achievement of regulatory milestones and up to $70 million for the achievement of
        commercialization milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that GSK successfully commercializes under this alliance. From inception through December 2018, we have
        received more than $162 million in payments under this alliance with GSK. We will achieve the next payment of up to $25 million if GSK licenses a medicine under this program.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services
        for GSK. We determined the transaction price to be the $35 million upfront payments we received and allocated it to our single performance obligation. As we achieved milestone payments for our R&amp;D services, we included these amounts in our
        transaction price for our R&amp;D services performance obligation. We recognized revenue for our R&amp;D services performance obligation over our period of performance, which ended in March 2015. We do not have any remaining performance obligations
        under our collaboration with GSK, however we can still earn additional payments and royalties as GSK advances these medicines.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:9f2f4af4-0862-46fa-bbbc-e7a8155428d6">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with GSK (in millions,
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    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z408cc0a364db4242b301d284d3bf5931" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">17.5</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:fa86d43c-37cd-471e-b232-016b9c961993">
    <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did not have any deferred revenue from our relationship with GSK at December 31, 2018 or December 31, 2017.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:db09b0eb-c86d-4d0a-b344-2df69600e21d">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-40</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Janssen Biotech, Inc.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December&#160;2014, we entered into a collaboration agreement with Janssen Biotech, Inc. to discover and develop antisense
        medicines that can be locally administered, including oral delivery, to treat autoimmune disorders of the gastrointestinal tract. Janssen has the option to license medicines from us through the designation of a development candidate for up to three
        programs. Under our collaboration, Janssen licensed IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in July 2016 and IONIS-JBI2-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in November 2017. Janssen is currently conducting a Phase 1 study of IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-JBI2-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        is in preclinical development. Prior to option exercise we are responsible for the discovery activities to identify development candidates. If Janssen exercises an option for any of the programs, it will be responsible for the global development,
        regulatory and commercial activities under that program. Under the terms of the agreement, we received $35 million in upfront payments. We are eligible to receive up to more than $800 million in license fees and milestone payments for these
        programs, including up to $175 million for the achievement of development milestones, up to $440 million for the achievement of regulatory milestones and up to $180 million for the achievement of commercialization milestones. From inception through
        December 2018, we have received over $75 million, including $15 million in license fees when Janssen licensed IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and IONIS-JBI2-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> from us. We also received $5 million in January 2018 for the initiation of a
        Phase 1 study of IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>in late 2017. In addition, we are eligible to receive tiered royalties up to the near teens on net sales from any medicines resulting from this collaboration. We will achieve the next payment of $5
        million if Janssen continues to advance a target under this collaboration.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services
        for Janssen. We determined the transaction price to be the $35 million upfront payments we received. We allocated the <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$35 million</font> to our single performance
        obligation. As we achieved milestone payments for our R&amp;D services, we included these amounts in our transaction price for our R&amp;D services performance obligation. We recognized revenue for our R&amp;D services performance obligation over
        our period of performance, which ended in November 2017.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We identified separate performance obligations each time Janssen licensed one of our medicines under our collaboration
        because the licenses we granted to Janssen were distinct from our other performance obligations. We recognized the $10 million license fee for IONIS-JBI1-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in July 2016 and $5 million for the license of IONIS-JBI2-2.5<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in
        November 2017, because Janssen had full use of the licenses without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the licenses after we delivered them to Janssen.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:f9f3e00b-631f-4683-863e-6a689da8203f">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Janssen (in
      millions, except percentage amounts):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="ze17541a6fb3144dd9610badb5fadcb6f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6.6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">36.0</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24.8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:dbcc6e5a-6666-4810-a02c-eef8d868f1c6">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We did not have any deferred revenue from our relationship with Janssen at December 31, 2018 and 2017.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:b21bc324-0013-4304-86f1-b8382937bcca">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Roche</div>
    <div><br>
    </div>
    <div style="text-align: left; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Huntington&#8217;s Disease</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In April&#160;2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to
        develop treatments for Huntington&#8217;s disease, or HD, based on our antisense technology. Roche had the option to license the medicines from us through the completion of the first Phase 1 trial. Under the agreement, we are responsible for the
        discovery and development of an antisense medicine targeting huntingtin, or HTT, protein. We evaluated a medicine targeting HTT, IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, in a Phase 1/2 clinical study in people with early stage HD.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>and





        is now responsible for the global development, regulatory and commercialization activities for IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. Under the terms of the agreement, we received an upfront payment of $30 million in April&#160;2013.&#160;In December 2016, we updated
        development activities for IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and as a result we were eligible for an additional $3 million payment, which we achieved in 2017. We are eligible to receive up to $365 million in a license fee and milestone payments including up
        to $70 million for the achievement of development milestones, up to $170 million for the achievement of regulatory milestones and up to $80 million for the achievement of commercialization milestones. In addition, we are eligible to receive up to
        $136.5 million in milestone payments for each additional medicine successfully developed.&#160;We are also eligible to receive tiered royalties up to the mid-teens on any net sales of any product resulting from this alliance. From inception through
        December 2018, we have received over $112 million in upfront fees, milestone payments and license fees for advancing IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, not including $35 million in milestone payments we earned in the first quarter of 2019 when Roche dosed the
        first patient in a Phase 3 study for IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. We will achieve the next payment of $15 million if Roche advances IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services
        for Roche. We determined the transaction price to be the $30 million upfront payment we received and allocated it to our single performance obligation. As we achieved milestone payments for our R&amp;D services, we included these amounts in our
        transaction price for our R&amp;D services performance obligation. We recognized revenue for our R&amp;D services performance obligation over our period of performance, which ended in September 2017.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-41</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We identified a second performance obligation upon Roche&#8217;s license of IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in the fourth quarter of 2017
        because the license we granted to Roche is distinct from our other performance obligation. We recognized the $45 million license fee for IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> as revenue at that time because Roche had full use of the license without any continuing
        involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Roche.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not have any remaining performance obligations related to IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> under this collaboration with
        Roche, however we can still earn additional payments and royalties as Roche advances IONIS-HTT<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times,
          serif;">IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="background-color: #FBFBFB;">Rx</font></sub><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for Complement-Mediated Diseases</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In October 2018, we entered into a
          collaboration agreement with Roche to</font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> develop IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;">&#160;for the treatment of complement-mediated diseases. The first indication we plan to pursue is the treatment of patients with Geographic Atrophy, or GA, the advanced stage of dry age-related macular degeneration, or AMD. We
          are responsible for conducting a Phase 2 study in patients with dry AMD. In addition, we are exploring the medicine in a severe and rare renal indication.&#160;</font>Roche<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times
          New Roman', Times, serif;">&#160;has the option to license IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="background-color: #FBFBFB;">Rx</font></sub><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;at the
          completion of these studies. Upon licensing,&#160;</font>Roche <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">will be responsible for all further global development, regulatory and
          commercialization activities and costs.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of
          this agreement, we received a&#160;</font>$75 million<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;upfront payment in October 2018. We are eligible to receive up to&#160;</font>$684 million<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;in development, regulatory and sales milestone payments and license fees. In addition, we are also eligible to receive tiered royalties from the
          high teens to twenty percent on net sales. We will achieve the next payment of $20 million when we advance </font>the Phase 2 study in patients with dry AMD<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman',
          Times, serif;">.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services
        for Roche. We determined the transaction price to be the $75 million upfront payment we received and allocated it to our single performance obligation. We are recognizing revenue for our R&amp;D services performance obligation as we perform
        services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently estimate we
          will satisfy our performance obligation in </font>December 2022.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:9f7f8994-0cf3-4186-bd60-f221a4b72939">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Roche (in millions,
      except percentage amounts):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zc3f3d360d97541dcbae58b9353f6da4a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="10" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8.3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">55.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:c85e1a08-6482-4ad4-ae0e-01a40307efc3">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our </font>consolidated balance sheet at <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">December 31, 2018 included deferred revenue of $72.6 million related to our relationship with Roche. We did not have any deferred revenue related to our relationship with Roche
        at December 31, 2017.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:fafda14b-c7b2-43a2-aaf4-37a70c79fb8b">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;">Akcea Collaborations</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following collaboration agreements relate to Akcea, our majority-owned affiliate. Our consolidated results include all
        the revenue earned and cash received under these collaboration agreements. We reflect the noncontrolling interest attributable to other owners of Akcea&#8217;s common stock in a separate line on the statement of operations and in a separate line within
        stockholders&#8217; equity in our consolidated balance sheet.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Novartis</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2017, we and Akcea initiated a collaboration with Novartis to develop and commercialize AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>
        and AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">&#160;</sub>Under the collaboration agreement, Novartis has an exclusive option to further develop and commercialize AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. Akcea is responsible for completing
        a Phase 2 program, conducting an end-of-Phase 2 meeting with the FDA and providing initial quantities of API for each medicine. If Novartis exercises an option for either of these medicines, Novartis will be responsible for all further global
        development, regulatory and co-commercialization activities and costs for such medicine.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea received a $75 million upfront payment in the first quarter of 2017, of which it retained $60 million and paid us
        $15 million as a sublicense fee. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2019, Novartis licensed AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and we earned a $150 million license fee. Akcea will pay us $75
        million as a sublicense fee in 2.8 million shares of Akcea common stock. Novartis is responsible for conducting and funding all future development, regulatory and commercialization activities for AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, including a global
        pivotal cardiovascular outcomes study, for which planning and initiation activities are underway.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>If Novartis exercises its option for AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>,
        Novartis will pay Akcea a license fee equal to $150 million. In addition, for AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, Akcea is eligible to receive up to $675 million in milestone payments, including $25 million for the achievement of a development milestone,
        up to $290 million for the achievement of regulatory milestones and up to $360 million for the achievement of commercialization milestones. In addition, for AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, Akcea is eligible to receive up to $530 million in milestone
        payments, including $25 million for the achievement of a development milestone, up to $240 million for the achievement of regulatory milestones and up to $265 million for the achievement of commercialization milestones. Akcea is also eligible to
        receive tiered royalties in the mid-teens to low 20 percent range on net sales of AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. Akcea will pay 50 percent of these license fees, milestone payments and royalties to us as a sublicense
        fee.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>In connection with Novartis&#8217; license of AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, Akcea and Novartis established a more definitive framework under which the companies would
        negotiate the co-commercialization of AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in selected markets. Included in this framework is an option by which Novartis could solely commercialize AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in exchange for Novartis paying Akcea increased
        commercial milestone payments based on sales of AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> Akcea may co-commercialize IONIS-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt;
          font-family: 'Times New Roman', Times, serif;"> if licensed and commercialized by Novartis in selected markets through its specialized sales force under terms and conditions to be negotiated with Novartis in the future.</font></font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-42</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6
        million shares of our common stock for $100 million in the first quarter of 2017. As part of the SPA, Novartis was required to purchase $50 million of Akcea&#8217;s common stock at the IPO price or our common stock at a premium if an IPO did not occur by
        April 2018. Under the SPA, in July 2017, Novartis purchased $50 million of Akcea&#8217;s common stock in a separate private placement concurrent with the completion of its IPO at a price per share equal to the IPO price.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified four separate performance obligations:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z88f0e8f2aa8d438d8450380c39594dbf" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D services for AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zaf41fe86b97b4cb9a75610133bac102c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D services for AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z89e2d0e9ff5c4fb38ea90d4f7e74365f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">API for AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z74f6bcaacbc14416b69b076796cf7f25" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">API for AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We determined that the R&amp;D services for each medicine and the API for each medicine were distinct from our other
        performance obligations.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We determined our transaction price to be $108.4 million, comprised of the following:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zecae9911c1994c6b8fde7eeb7e508f34" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$75 million from the upfront payment;</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z2e7f764f5fbb41c992cf34e92646503a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$28.4 million for the premium paid by Novartis for its purchase of our common stock at a premium in the first quarter of 2017; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zf541a64b633f49c89227e92391ea611e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$5.0 million for the potential premium Novartis would have paid if they purchased our common stock in the future.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as
        follows:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zaee284a1b5c64f84ab4258998ecf44c3" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$64.0 million for the R&amp;D services for </font><font style="font-size: 10pt;
                      font-family: 'Times New Roman', Times, serif;">AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-family: 'Times New Roman';">Rx</font></sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">;</font></font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z9234bd3429c74be2bd356ed6cd783f06" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$40.1 million for the R&amp;D services for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-family: 'Times New Roman';">Rx</font></sub>; </font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z74d807426ed24f2faec9c042798a600d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$1.5</font> million for the delivery of AKCEA-APO(a)-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> API; and</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zc88a340467c347d3b9e399d5667249e6" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 36pt;"></td>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$2.8</font> million for the delivery of AKCEA-APOCIII-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> API.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are recognizing revenue related to the
          R&amp;D services for the AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times,
          serif;"> performance obligations as we perform services </font>based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation<font style="font-size: 10pt; font-family: 'Times
          New Roman', Times, serif;">. </font>We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> satisfied the significant portion of our performance obligation for AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size:
          10pt; font-family: 'Times New Roman', Times, serif;"> in December 2018 and we currently estimate we will satisfy the remainder by mid-2019. </font>We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently estimate
          we will satisfy the significant portion of our performance obligation for AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> by mid-2020 with the remainder by the end of 2019. We
          recognized the amount attributed to the API supply for AKCEA-APO(a)-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> when we delivered it to Novartis in 2017. We recognized the amount attributed
          to the API supply for AKCEA-APOCIII-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> when we delivered it to Novartis in May 2018.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea is responsible for the development activities under this collaboration. As such, Akcea is recognizing the associated
        revenue in its statement of operations, and we reflect all of Akcea&#8217;s revenue in our consolidated results. Akcea pays us sublicense fees for payments that it receives under the collaboration and we recognize those fees as revenue in our Ionis Core
        operating segment results and Akcea recognizes the fees as R&amp;D expense. In our consolidated results, we eliminate this sublicense revenue and expense. Any cash Akcea receives is included in our consolidated balance sheet.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:c1b009fc-aac2-44fd-b955-e8435944483a">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018 and 2017, we earned the following revenue from our relationship with Novartis (in millions,
      except percentage amounts):</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z5f2b5f1b99e34d89981dc76eea2882e0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="6" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#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: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50.6</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43.4</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:9002094d-5510-4e2e-bbd3-374a415baab8">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our </font>consolidated balance sheet at <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">December 31, 2018 and 2017 included deferred revenue of $28.8 million and $70.7 million, respectively, related to our relationship with Novartis.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:98792d7e-d0e5-413d-b110-ee61770320d0">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">PTC Therapeutics</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In August 2018, Akcea entered into an exclusive license agreement with PTC Therapeutics to commercialize TEGSEDI and
        WAYLIVRA in Latin America. Under the license agreement, Akcea is eligible to receive up to $26 million in payments, including $12 million which it received in the third quarter of 2018, $6 million upon the earlier of FDA or EMA approval of WAYLIVRA
        and up to $8 million for regulatory milestones. Akcea is eligible to receive royalties from PTC in the mid-20 percent range on net sales in Latin America for each medicine.&#160;PTC&#8217;s obligation to pay Akcea royalties begins on the earlier of 12 months
        after the first commercial sale of a product in&#160;Brazil&#160;or the date that PTC recognizes revenue of at least&#160;$10 million&#160;in Latin America. Consistent with the agreements between Ionis and Akcea, the companies will share all payments, including
        royalties.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified two performance obligations, which were the licenses Akcea
        granted to PTC to commercialize TEGSEDI and WAYLIVRA in Latin America in the third quarter of 2018. Akcea recognized $12 million in license fee revenue at that time because PTC had full use of both licenses without any continuing involvement from
        Akcea. Akcea does not have any remaining performance obligations under its collaboration with PTC. Akcea can still earn additional payments and royalties as PTC commercializes the medicines.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-43</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea was responsible for the activities under this collaboration. As such, Akcea is recognizing the associated revenue in
        its statement of operations, and we reflect all of Akcea&#8217;s revenue in our consolidated results. Akcea pays us sublicense fees for payments that it receives under the collaboration and we recognize those fees as revenue in our Ionis Core operating
        segment results and Akcea recognizes the fees as SG&amp;A expense. For example, during the third quarter of 2018, we recognized $7.2 million of sublicense revenue in our Ionis Core operating segment results related to our portion of the PTC license
        fee Akcea paid us. In our consolidated results, we eliminate this sublicense revenue and expense. Any cash Akcea receives is included in our consolidated balance sheet.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:32004306-b835-4851-9a62-2782bb515a60">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our consolidated balance sheet at December 31, 2018 and 2017 did not include any deferred revenue related to our relationship with PTC.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:55312cce-5fb8-406d-9747-754e5b46c7d9">
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">External Project Funding</div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are pursuing discovery and development projects that provide us with new therapeutic applications for antisense
          medicines. These programs represent opportunities for us and our technology. In some cases, we have funded these studies through support from our partners or disease advocacy groups and foundations. Our External Project Funding partners include
          the following:</font></div>
      <div><br>
      </div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z573888761e0844998ed6f9368e994303" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"></td>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">CHDI Foundation</font><font style="font-size: 10pt;
                        font-family: 'Times New Roman', Times, serif;">- </font>Through our development collaboration, CHDI provided financial and scientific support to our Huntington&#8217;s disease drug discovery program. W<font style="font-size: 10pt;
                        font-family: 'Times New Roman', Times, serif;">e have reimbursed CHDI for its support of our Huntington&#8217;s disease program out of the payments we receive from Roche.</font></font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="ze0afc93206904ff5a35721e78fea2349" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"></td>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Cystic Fibrosis Foundation</font>- We received upfront
                      funding from the Cystic Fibrosis Foundation to discover and advance a medicine for the treatment of cystic fibrosis. In exchange for this funding, we are obligated to pay the Cystic Fibrosis Foundation up to $18 million upon achieving
                      specific regulatory and sales events if we advance a medicine under our collaboration.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zbec7b5496f7d4367a5bfda820bdafc0c" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"></td>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">The Ludwig Institute; Center for Neurological Studies- </font>We





                      have a collaboration with the Ludwig Institute, the Center for Neurological Studies and researchers to discover and develop antisense medicines for ALS and other neurodegenerative diseases. Under this agreement, we agreed to pay the
                      Ludwig Institute and the Center for Neurological Studies modest milestone payments and royalties on any antisense medicines resulting from the collaboration.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:7b5912ea-9921-4973-8c4d-86c677eae942">
    <div style="background-color: #FFFFFF;">
      <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">In-Licensing Agreements</div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our in-licensing arrangements include:</font></div>
    </div>
    <div style="background-color: #FFFFFF;">
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zfb81ee856b624a8f967dbd3971f0eba4" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"></td>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">University of Massachusetts- </font>We have a license
                      agreement with the University of Massachusetts under which we acquired an exclusive license to the University of Massachusetts&#8217; patent rights related to SPINRAZA. We paid the University of Massachusetts nominal amounts for license
                      fees and milestone payments we received. We also pay a low single digit royalty on net sales of SPINRAZA.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7782de54a1774d10925159ae5d615690" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"></td>
                <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Cold Spring Harbor Laboratory-</font> We have a
                      collaboration and license agreement with the Cold Spring Harbor Laboratory under which we acquired an exclusive license to the Cold Spring Harbor Laboratory&#8217;s patent rights related to SPINRAZA. We paid Cold Spring Harbor Laboratory
                      nominal amounts for license fees and milestone payments we received in 2017 and a low single digit royalty on net sales of SPINRAZA. Additionally, we owe a low single digit royalty on future sales of SPINRAZA.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
    </div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:08c454d2-ebc3-4ff2-bc33-27f44329397b">
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">7. Segment Information and Concentration of Business Risk</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have two reportable segments Ionis Core
          and Akcea Therapeutics. </font>At December 31, 2018, we owned approximately 75 percent of Akcea.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> Segment income (loss) from operations includes revenue less operating
          expenses attributable to each segment.</font></font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In our Ionis Core segment we are exploiting our antisense technology to generate a broad pipeline of first-in-class and/or
        best-in-class medicines for us and our partners. Our Ionis Core segment generates revenue from a multifaceted partnering strategy.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea is </font>a biopharmaceutical company
        focused on developing and commercializing medicines to treat patients with rare and serious diseases<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</font></font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:980714f4-d1e3-46d7-9613-46bed5501e38">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-44</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following tables show our segment revenue and income
        (loss) from operations for </font>2018, 2017 and 2016<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> (in thousands), respectively.</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z452c2901f9a1444b95b519555c19fc29" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis Core</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Elimination of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Intercompany Activity</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Total</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top;">
            <div style="text-align: left; margin-left: 7.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">237,930</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">237,930</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">TEGSEDI product sales, net</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,237</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,237</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Licensing and other royalty revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,755</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,000</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,755</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; margin-left: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total commercial revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">240,685</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,237</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">254,922</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 7.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue under collaborative agreements</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">401,259</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50,630</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(107,137</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">344,752</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total segment revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">641,944</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">64,867</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(107,137</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">380,212</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">295,683</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(14,849</font></div>
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          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">661,046</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income (loss) from operations</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">261,732</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(230,816</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(92,288</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(61,372</font></div>
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        <tr>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017 (as revised)</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis Core</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea Therapeutics</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Elimination of</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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            <div style="text-align: left; margin-left: 7.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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          <td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112,540</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112,540</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Licensing and other royalty revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,474</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7,474</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total commercial revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120,014</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120,014</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; margin-left: 7.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue under collaborative agreements</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">405,171</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,401</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(54,407</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">394,165</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total segment revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">525,185</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,401</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(54,407</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">514,179</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total operating expenses</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">373,788</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">163,871</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(54,527</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">483,132</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income (loss) from operations</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">151,397</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(120,470</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">31,047</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016 (as revised)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis Core</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea Therapeutics</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Elimination of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Intercompany Activity</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top;">
            <div style="text-align: left; margin-left: 7.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">883</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">883</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Licensing and other royalty revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,884</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,884</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total commercial revenue</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,767</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,767</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: left; margin-left: 7.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue under collaborative agreements</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">362,657</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,648</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">350,009</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total segment revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">385,424</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,648</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">372,776</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total operating expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">322,192</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">83,512</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,768</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">392,936</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income (loss) from operations</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">63,232</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(83,512</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">120</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(20,160</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following table shows our total assets by segment at December 31, 2018 and 2017 (in thousands), respectively.</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z4a4ce716d61d4ffda9ab024150c7c80d" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Total Assets</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis Core</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea Therapeutics</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Elimination of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Intercompany Activity</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Total</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">December 31, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,975,491</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">365,261</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(672,968</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,667,784</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">December 31, 2017 (as revised)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,342,578</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">268,804</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(288,608</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,322,774</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:62360613-0ad6-4717-9847-e19c33090189">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Contracts receivables at December 31, 2018 and December&#160;31, 2017 were comprised of approximately 99 percent and 84&#160; percent for each
      year from four and two significant partners, respectively.</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:0100dde7-4348-4563-afa5-9b181d3af300">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">8. Employment Benefits</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have an employee 401(k) salary deferral plan, covering all employees. Employees could make contributions by withholding
        a percentage of their salary up to the IRS annual limit $18,500 and $24,500 in 2018 for employees under 50 years old and employees 50 years old or over, respectively. We made approximately $5.7 million, $3.0 million and $1.7 million in matching
        contributions for the years ended December 31, 2018, 2017 and 2016, respectively.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:e8a006af-517e-4a98-8eca-20b9e75664ca">
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-45</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">9. Legal Proceedings</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we
        evaluate the status of each legal matter and assess our potential financial exposure. If the potential loss from any legal proceeding is considered probable and the amount can be reasonably estimated, we accrue a liability for the estimated loss.
        Significant judgment is required to determine the probability of a loss and whether the amount of the loss is reasonably estimable. The outcome of any proceeding is not determinable in advance. As a result, the assessment of a potential liability
        and the amount of accruals recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the potential liability related to the legal proceeding, and may revise our estimates.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Gilead Litigation</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In August 2013, Gilead Sciences Inc. filed a suit in the U.S. District Court of Northern District of California related to
        U.S. Patent Nos. 7,105,499 and 8,481,712, which are jointly owned by Merck Sharp &amp; Dohme Corp. and Ionis Pharmaceuticals, Inc.&#160;In the suit Gilead asked the court to determine that Gilead&#8217;s activities do not infringe any valid claim of the named
        patents and that the patents are not valid. We and Merck Sharp &amp; Dohme Corp. filed our answer denying Gilead&#8217;s noninfringement and invalidity contentions, contending that Gilead&#8217;s commercial sale and offer for sale of sofosbuvir prior to the
        expiration of the &#8216;499 and &#8216;712 patents infringes those patents, and requesting monetary damages to compensate for such infringement. In the trial for this case held in March 2016, the jury upheld all <font style="font-size: 10pt; font-family:
          'Times New Roman', Times, serif;">ten</font> of the asserted claims of the patents-in-suit. The jury then decided that we and Merck are entitled to <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">four percent of $5 </font>billion





        in past sales of sofosbuvir. Gilead has stated it would appeal the jury&#8217;s finding of validity. In the meantime, Gilead asserted <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">two </font>additional non-jury defenses:
        waiver and unclean hands. Although the judge rejected the waiver defense, she granted Gilead&#8217;s motion claiming that the patents are unenforceable against it under the doctrine of unclean hands. We believe this ruling is contrary to the relevant law
        and the facts of the case. Accordingly, in July 2016, together with Merck we appealed the decision to the Court of Appeals for the Federal Circuit. Gilead cross-appealed on the issue of validity. In April 2018, the Court of Appeals issued its
        ruling affirming the District Court&#8217;s finding of unenforceability based on unclean hands.&#160;Having upheld the ruling that the patents are unenforceable against Gilead, the court did not reach the question of validity. In September 2018, we filed a
        petition requesting a hearing before the Supreme Court, asserting that it was improper for the trial court to overturn the jury verdict on the basis of the equitable defense of unclean hands. In January 2019, the Supreme Court denied our petition.
        Under our agreement with Merck, Merck is responsible for the costs of this suit.</font></div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:e98dc650-c9ab-417b-9491-f1a75450e409">
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">10. Quarterly Financial Data (Unaudited)</div>
    <div><br>
    </div>
  </div>
  <div id="TRGRSegment:867bad6b-7f03-4324-87a0-a1ac5799eba2">
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following financial information reflects all normal recurring adjustments, which are, in the opinion of management, necessary for a
      fair statement of the results of the interim periods. Summarized quarterly data for the years ended December 31, 2018 and 2017 are as follows (in thousands, except per share data).</div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2018 Quarters</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">First</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Second</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Third</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Fourth</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">144,419</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">117,747</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">145,395</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">192,113</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Operating expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">147,720</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">168,028</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">163,967</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">181,331</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income (loss) from operations</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3,301</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(50,281</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(18,572</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,782</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(10,812</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(56,573</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(20,365</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">302,735</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,420</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(40,358</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4,559</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">320,078</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net income (loss) per share (1) (2)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.01</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.29</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.03</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.32</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Diluted net income (loss) per share (1) (3)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.01</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.29</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.03</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.21</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
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    <table cellspacing="0" cellpadding="0" id="z24b27bd10b314d31a57ad462bb41dc1f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017 Quarters (as revised)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">First</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Second</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Third</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Fourth</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Revenue</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">115,800</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">112,273</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">118,314</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">167,792</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Operating expenses</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">96,315</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">105,823</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">107,002</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">173,992</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income (loss) from operations</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">19,485</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">6,450</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,312</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(6,200</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,964</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3,085</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(7,493</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(9,169</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income (loss) attributable to Ionis Pharmaceutical, Inc. common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,964</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3,085</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2,611</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2,922</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net income (loss) per share (1) (2)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.07</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.02</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.02</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.03</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;">
            <div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Diluted net income (loss) per share (1) (3)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.07</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.02</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.02</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.03</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>

    </table>
    <div style="text-align: justify; text-indent: 500.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"></font><br>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z4b6cab98c5664681afeac67d0162f086" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We computed net income (loss) per share independently for each of the quarters presented. Therefore, the sum of the quarterly net income (loss) per share will
                    not necessarily equal the total for the year.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zccd62a48ad664d52911ab417c803609f" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As discussed in Note 1, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Organization and Significant
                      Accounting Policies, </font>we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period.
                    Our basic net income (loss) per share calculation for each of the quarters in 2018 and for the third and fourth quarters of 2017 considered our net income for Ionis on a stand-alone basis plus our share of Akcea&#8217;s net loss for the
                    period. To calculate the portion of Akcea&#8217;s net loss attributable to our ownership, we multiplied Akcea&#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our&#160;total net
                    income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements
                    of operations.</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-46</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our basic net income (loss) per share for each quarter in 2018 was calculated as follows (in thousands, except per share
        amounts):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zdd8cc2626f434e6aafdf83d7d6632725" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Three Months Ended March 31, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Average Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Owned in Akcea</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis</font>&#8217;<font style="font-size:
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Common shares</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">45,448</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.44</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(19,997</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s net loss attributable to our ownership</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(19,997</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis&#8217; stand-alone net income</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,785</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net loss available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,212</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Weighted average shares outstanding</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">125,330</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net loss per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.01</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>

    </table>
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    <table cellspacing="0" cellpadding="0" id="z189507495bb3421fb6eda8f95c715479" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Three Months Ended June 30, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Average Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Owned in Akcea</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Net Income (Loss)</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Per Share</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis</font>&#8217;<font style="font-size:
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Common shares</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">60,832</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.72</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(43,814</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s net loss attributable to our ownership</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(43,814</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis&#8217; stand-alone net income</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5,882</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net loss available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(37,932</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Weighted average shares outstanding</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">128,712</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net loss per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.29</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Three Months Ended September 30, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Average Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Owned in Akcea</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Net Income (Loss)</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Per Share</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis</font>&#8217;<font style="font-size:
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Common shares</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">65,538</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.73</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(47,789</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s net loss attributable to our ownership</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(47,789</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis&#8217; stand-alone net income</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">43,226</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net loss available to Ionis common stockholders</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4,563</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Weighted average shares outstanding</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">137,346</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net loss per share</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
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            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.03</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
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        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Three Months Ended December 31, 2018</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Average Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Owned in Akcea</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Per Share</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis</font>&#8217;<font style="font-size:
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Common shares</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">67,130</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.79</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(53,219</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s net loss attributable to our ownership</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(53,219</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis&#8217; stand-alone net income</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">372,913</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">319,694</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Weighted average shares outstanding</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">137,699</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net income per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.32</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
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    </table>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Prior to Akcea&#8217;s IPO in July 2017, we owned Akcea series A convertible preferred stock, which included a six percent
        cumulative dividend. Upon completion of Akcea&#8217;s IPO in July 2017, our preferred stock was converted into common stock on a 1:1 basis. The preferred stock dividend was not paid at the IPO because the IPO was not a liquidation event or a change in
        control. During the three months ended September 30, 2017, Akcea used a two-class method to compute its net income (loss) per share because it had both common and preferred shares outstanding during the periods. The two-class method required Akcea
        to calculate its net income (loss) per share&#160;for each class of stock by dividing total distributable losses applicable to preferred and common stock, including the&#160;six percent&#160;cumulative dividend contractually due to series A convertible preferred
        shareholders, by the weighted-average of preferred and common shares outstanding during the requisite period. Since Akcea used the two-class method, accounting rules required us to include our portion of Akcea&#8217;s net income (loss) per share for both
        Akcea&#8217;s common and preferred shares that we owned in our calculation of basic and diluted net income (loss) per share for the three months ended September 30, 2017.</font></div>
    <div><br>
    </div>
    <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 8pt; font-weight: normal; font-style: normal;">F-47</font></div>
      <div id="DSPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our basic net income (loss) per share for the three months ended <font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;">September 30, 2017</font> was calculated as follows (in thousands, except per share amounts):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zf9e992c00b9a45e9bde901a922513c4e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Three Months Ended September 30, 2017</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Average Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Owned in Akcea</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
                  10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Net Loss</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Per Share</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis</font>&#8217;</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Portion of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
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          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Common shares</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">36,556</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.33</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,063</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Preferred shares</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5,651</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.01</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(57</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s net loss attributable to our ownership</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,120</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis&#8217; stand-alone net income</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,144</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net loss available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,976</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Weighted average shares outstanding</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">124,370</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net loss per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.02</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our basic net income (loss) per share for the three months ended <font style="font-size: 10pt; font-family: 'Times New
          Roman', Times, serif;">December 30, 2017</font> was calculated as follows (in thousands, except per share amounts):</font></div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z0eb6d1b151014946a24eedddd1f97cd0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Three Months Ended December 31, 2017</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Weighted</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Average Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Owned in Akcea</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
                  10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Net Loss</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Per Share</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Ionis</font>&#8217;</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Portion of</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Akcea</font>&#8217;<font style="font-size:
                  10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">s Net Loss</font></font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Common shares</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">45,448</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.30</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(13,634</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea&#8217;s net loss attributable to our ownership</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(13,634</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis&#8217; stand-alone net income</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,510</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net loss available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3,124</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Weighted average shares outstanding</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">124,818</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Basic net loss per share</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(0.03</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify;">
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="ze3fdebfc22ec4506942199fb10800a8e" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

            <tr>
              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3)</font></td>
              <td style="width: auto; vertical-align: top; text-align: justify;">
                <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For the three months ended December 31, 2018, we had net income available to Ionis common stockholders. As a result, we computed diluted net income per share
                    using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods. Diluted common equivalent shares for the three months ended December 31, 2018 consisted of the following (in
                    thousands except per share amounts):</font></div>
              </td>
            </tr>

        </table>
      </div>
    </div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="zf79c3118631b4c83a364cd70083778c3" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Three Months Ended December 31, 2018</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Numerator)</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Denominator)</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Amount</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income available to Ionis common stockholders</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.32</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Effect of dilutive securities:</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable upon exercise of stock options</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,254</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable upon restricted stock award issuance</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">636</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable related to our ESPP</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable related to our 1 percent convertible notes</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,745</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10,260</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income available to Ionis common stockholders, plus assumed conversions</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">330,439</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">149,856</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2.21</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For the three months ended March 31, 2017, we owned 100 percent of Akcea. As a result, we did not have to adjust our
        earnings per share calculation. For the three months ended March 31, 2017, we had net income. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding
        during those periods. Diluted common equivalent shares for the three months ended March 31, 2017 consisted of the following (in thousands except per share amounts):</font></div>
    <div><br>
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    <table cellspacing="0" cellpadding="0" id="z59ef228eba32433782886daec8ea3e5a" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

        <tr>
          <td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Three Months Ended March 31, 2017</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Income</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Numerator)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Shares</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Denominator)</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom; border-bottom: #000000 solid 2px;">
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Per-Share</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Amount</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" colspan="2" style="vertical-align: bottom;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net income available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,964</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td>
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        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Effect of dilutive securities:</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable upon exercise of stock options</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable upon restricted stock award issuance</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">377</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;">
            <div style="text-align: left; text-indent: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Shares issuable related to our ESPP</font></div>
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          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">60</font></div>
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          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td>
        </tr>
        <tr>
          <td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;">
            <div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income available to Ionis common stockholders</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,964</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">124,972</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
          <td valign="bottom" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div>
          </td>
          <td valign="bottom" colspan="1" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">
            <div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0.07</font></div>
          </td>
          <td valign="bottom" nowrap="nowrap" colspan="1" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td>
        </tr>

    </table>
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    </div>
    <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For the three months ended March 31, 2017, the calculation excluded the 1 percent and 2&#190; percent notes because the effect on
        diluted earnings per share was anti-dilutive.</font></div>
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  <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-size: 8pt; font-weight: normal; font-style: normal; font-family: &quot;Times New Roman&quot;,Times,serif;">F-48</font></div>
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<DOCUMENT>
<TYPE>EX-10.67
<SEQUENCE>2
<FILENAME>exhibit10_67.htm
<DESCRIPTION>EXHIBIT 10.67
<TEXT>
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                <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps; font-weight: bold;">Confidential</div>
              </td>
              <td style="width: 50.00%;">
                <div>
                  <div style="text-align: right; font-family: &quot;Times New Roman&quot;; font-size: 10pt; font-variant: small-caps; font-weight: bold;">Execution Copy</div>
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          <div style="text-align: right; margin-right: 7.2pt; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps; font-weight: bold;"> <br>
          </div>
          <div style="text-align: right; font-family: &quot;Times New Roman&quot;; font-size: 10pt; font-variant: small-caps; font-weight: bold;">CONFIDENTIAL TREATMENT REQUESTED<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><br>
            </font>UNDER 17 C.F.R. &#167;&#167; 200.80(b)(4) and 240.24B-2</div>
          <div style="text-align: right; margin-right: 7.2pt; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps; font-weight: bold;"> <br>
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          <div style="text-align: right; font-family: &quot;Times New Roman&quot;; font-size: 10pt; font-variant: small-caps; font-weight: bold;">
            <div style="text-align: right; font-family: &quot;Times New Roman&quot;; font-size: 10pt; font-variant: small-caps; font-weight: bold;">Exhibit 10.67</div>
          </div>
        </div>
        <div> <br>
        </div>
      </div>
      <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps; font-weight: bold;">Factor B Development Collaboration, Option and License Agreement</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"> <br>
        </font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">Among</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">Ionis Pharmaceuticals, Inc.,</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">And</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">F. Hoffmann-La Roche Ltd</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">And</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">Hoffmann-La Roche Inc.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"> <br>
        </font></div>
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        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
        </font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">FACTOR B DEVELOPMENT COLLABORATION, OPTION AND LICENSE AGREEMENT</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">This FACTOR B DEVELOPMENT COLLABORATION, OPTION AND LICENSE AGREEMENT (the &#8220;<font style="font-size: 10pt; font-family: 'Times New
            Roman'; font-weight: bold; font-style: italic;">Agreement</font>&#8221;) is entered into as of the 9<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup> day of October, 2018 (the &#8220;<font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Effective Date</font>&#8221;) by and among <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">Ionis Pharmaceuticals,
            Inc.</font>, a Delaware corporation, having its principal place of business at 2855 Gazelle Court, Carlsbad, California 92010 (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis</font>&#8221;),







          and<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche Basel</font>&#8221;)







          and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">Hoffmann-La Roche
            Inc.</font>,&#160; a New Jersey corporation, having its principal place of business at 150 Clove Road, Suite 8, Little Falls, New Jersey 07424 (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche







            US</font>&#8221;; Roche Basel and Roche US are collectively referred to as &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche</font>&#8221;). Roche and Ionis each may be referred to herein
          individually as a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Party</font>&#8221; or collectively as the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
            font-style: italic;">Parties</font>&#8221;.</font></div>
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      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">RECITALS</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">WHEREAS</font>, Ionis has expertise in discovering
          and developing antisense drugs, and is developing the antisense drug IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>;</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">WHEREAS</font>, Roche has expertise in developing
          and commercializing drugs, and Roche is interested in developing and commercializing IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>;</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">WHEREAS</font>, Roche desires Ionis to develop
          IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> through completion of a phase 2 trial in the ophthalmological indication of geographic atrophy and an anticipated phase 2a trial in [***] and grant Roche
          an option to obtain an exclusive license to develop and commercialize such drug;</font></div>
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      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">NOW, THEREFORE</font>, in consideration of the
          respective covenants, representations, warranties and agreements set forth herein, the Parties hereto agree as follows:</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 1.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">DEFINITIONS</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The terms used in this Agreement with initial letters capitalized, whether used in the singular or the plural, will have the meaning
          set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 1</u></font>, or if not listed in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 1</u></font>, the meaning designated in places throughout the Agreement.</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 2.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">AGREEMENT OVERVIEW</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The intent of the Collaboration is for the Parties to develop IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> for (i) the treatment of geographic atrophy (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">GA</font>&#8221;), and (ii)<font style="font-size: 10pt; font-family: 'Times New
            Roman'; font-weight: bold; font-style: italic;">&#160;</font>potentially the treatment of [***] (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">[***]</font>&#8221;).&#160; Ionis will Develop IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> through Completion of the Proposed Phase 2 Trials.&#160; Roche will have an Option to obtain an exclusive license to further Develop, Manufacture, and Commercialize
          IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>.&#160; Unless terminated earlier, the Option will be exercisable from any time the last patient specified in the most current version of the Development Plan
          (i.e. the initial Development Plan as modified by the JSC) has been enrolled in the Phase 2 GA Trial until the Option Deadline (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option
            Period</font>&#8221;). <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">&#160;</font>If Roche exercises its Option, Roche will be responsible for all further Development, Manufacturing and
          Commercializing activities related to the Products, except for any Phase 2 Trials then being conducted by Ionis under the Development Plan. <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">&#160;</font>The







          purpose of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 2</u></font> is to provide a high-level overview of the roles, responsibilities, rights and obligations of each Party under this Agreement with regard to
          the Development and Commercialization of the Products, and therefore this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 2</u></font> is qualified in its entirety by the more detailed provisions of this Agreement set
          forth below.</font></div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">2</font></div>
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      </div>
      <div style="text-align: left;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 3.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">DEVELOPMENT COLLABORATION FOR IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">R</sub><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-family: 'Times New Roman Bold', serif;">x</font></sub></font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="za61c9ddd259046649b1ca450105e4d9d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development Activities for IONIS-FB-L</u></font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;"><u>Rx</u></font></sub><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">.</font>&#160; The Parties will Develop IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> under a development plan agreed between the Parties or as may be amended by the JSC from time to time, which covers all Clinical Studies to be conducted
                      through completion of the Development activities necessary to obtain Approval of a Product in at least one (1) Indication (such plan, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style:
                        italic;">Development Plan</font>&#8221;, and such program, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Development Program</font>&#8221;).&#160; Each Party will use Commercially
                      Reasonable Efforts to conduct the Development activities assigned to such Party under, and in accordance with, the Development Plan; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that</font>
                      neither Roche nor Ionis will have any obligation to perform any activity that, after having consulted the JSC or the applicable JDC, 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z9b4fc00860e8425d81688cc404b7b075" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development Plan</u></font>.&#160; As of the Effective Date, the Parties have agreed to an
                      initial Development Plan, which includes a clinical trial protocol synopsis for the Phase 2 GA Trial (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">GA Protocol</font>&#8221;) and
                      a general outline for the Phase 2 [***] Trial.&#160; Until the sooner of, the Development Plan is replaced by the IDCP under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.1.1</u></font> or the JSC is
                      dissolved, the Development Plan will be updated at least annually by the JSC and the applicable JDC.&#160; Subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)(ii)</u></font> below, any changes to
                      the Development Plan must be agreed to by the JSC and the applicable JDC.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zefac16ed74af437bb96db23f70f76b7e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Proposed Phase 2 Trials</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zdc13ed3a1aca440b94deb3a71c1ff141" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Phase 2 GA Trial</u></font>.&#160; Ionis will conduct the Phase 2 GA Trial under the GA
                      Protocol.&#160; Ionis will use Commercially Reasonable Efforts to meet the timeline for the Phase 2 GA Trial as determined by the JSC and the applicable JDC, including to meet the Specific Performance Milestone Events in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 2</u></font>.&#160; Ionis will keep Roche informed of the progress of such Phase 2 GA Trial through the JSC and applicable JDC.&#160; &#160; &#160; </font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z32a40014a3584ae1b07b50cd6aacf7c1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Phase 2 [***] Trial</u></font>.&#160; Ionis will conduct the Phase 2 [***] Trial under a
                      protocol to be finalized through the JSC and the applicable JDC.&#160; Ionis will use Commercially Reasonable Efforts to meet the timeline for the Phase 2 [***] Trial as determined by the JSC and the applicable JDC, including to meet the
                      Specific Performance Milestone Events in<font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u> Appendix</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 2</u></font>.&#160;
                      Ionis will keep Roche informed of the progress of such Phase 2 [***] through the JSC and applicable JDC.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">3</font></div>
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z639c9945d7c94e988271ecd5a99b11c6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Phase 2 Trial Data Package and Interim Data</u></font>.&#160; Promptly after conducting
                      interim data analysis related to either the Phase 2 GA Trial or the Phase 2 [***] Trial (if any), Ionis will provide to Roche a copy of its analyses and the underlying data sufficient for Roche to conduct a pharmacokinetics and/or
                      pharmacodynamics analysis, and ongoing safety data (which will be provided by Ionis to Roche on an ongoing basis). Once available to Ionis, Ionis will promptly deliver to Roche the Phase 2 Trial Data Package.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zbece3ceacb4a4e54a1ae3d74e5383233" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Additional Development of IONIS-FB-L</u></font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;"><u>Rx</u></font></sub>.&#160; The Parties are discussing additional Development (clinical or non-clinical) of IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and will continue such discussions in good faith prior to Option exercise.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zbc9e9d8ec8eb49a6b3cdb5296757813d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, before Option exercise, Ionis and Roche agree that Ionis will conduct an additional Phase 2 Trial or any additional earlier stage Clinical Study for the Product, then
                      the Parties will share the costs of such additional Phase 2 Trial and negotiate in good faith the design and reimbursement terms for such Clinical Study(ies), including a budget, payment schedule, an appropriate methodology to
                      allocate the costs of such Clinical Study(ies), and who will supply clinical-grade API and Finished Drug Product, and the JSC and the applicable JDC will revise the Development Plan to include a clinical trial protocol synopsis for
                      each such Clinical Study.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="za2e120a36d42495191d7e634c24d7118" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, before Option exercise, Ionis (but not Roche) would like to conduct a phase 2b trial in [***] (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
                        font-weight: bold; font-style: italic;">Phase 2b [***] Trial</font>&#8221;), then [***] such Phase 2b [***] Trial, and upon Initiation of a Registration-Directed Trial for [***] after Option exercise, Roche will pay to Ionis [***] within
                      [***] days after Initiation of a Registration-Directed Trial for [***] and Roche&#8217;s receipt of an invoice from Ionis. Initiation of the Registration-Directed Trial for [***] is at the sole discretion of Roche.&#160; For clarity, no such
                      payment will be required if Roche does not provide the Option Exercise Notification. For clarity, the payment in this clause (b) is not applicable to clauses (a) or (c).</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zb4fc995b35ff4b68ac0ac5b5f516b4f9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Roche would like Ionis to conduct the Phase 2b [***] Trial but Ionis is unable or unwilling to conduct such trial, then Roche may undertake such Phase 2b [***] under
                      Ionis&#8217; IND and Roche will pay [***] but may offset [***] of Roche&#8217;s reasonable costs incurred in running the Phase 2b [***] Trial before Option exercise against the next Post-Licensing Milestone Payment under <font style="font-size:
                        10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 1</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;">&#160;</font>of <font style="font-size: 10pt; font-family:
                        'Times New Roman';"><u>Section 9.4</u></font> that becomes due.&#160; Ionis will use Commercially Reasonable Efforts to comply with Roche&#8217;s reasonable requests for support regarding Regulatory Materials and interactions with Regulatory
                      Authorities and other activities required to conduct the Phase 2b [***] Trial under the Ionis IND.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">4</font></div>
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="zc707dc1453a745d4afc58df28f788ba0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Attaching Plans to JSC Minutes</u></font>.&#160; The JSC will attach each revised
                      Development Plan to the meeting minutes of the JSC.</font></div>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z5d2ceaf403064c4ba6b2b7ec1fdda3c9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development Plan Costs</u></font>. Before Option exercise, except as the Parties may
                      otherwise agree, Ionis will be responsible for all costs and expenses associated with the activities assigned to Ionis under the Development Plan, and Roche will be responsible for all costs and expenses associated with the activities
                      assigned to Roche under the Development Plan.&#160; Before Option exercise, if the Parties mutually agree to a material change to the Development Program (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>,
                      add a new arm or increase the maximum number of study subjects) or a Regulatory Authority requires Ionis to change the Development Program (each an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                        font-style: italic;">Approved Change</font>&#8221;), the Parties will share the Approved Change Costs (as defined below) as follows: </font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z3667f36b35e64d7fb6285b84a0ac5dc2" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If the Approved Change Costs are less than [***], then [***] will be responsible for the Approved Change Costs.</font></div>
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          </table>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z107c285147e0429aaf23e1bfc3f9fed5" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If the Approved Change Costs are [***]or higher and less than [***], then [***] will be responsible for the Approved Change Costs for the first [***] and [***] will be
                      responsible for the Approved Change Costs above [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zab4fd3528d174a5d884397ec32534a36" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If the Approved Change Costs are [***] or more, then each Party will be responsible for one half of the portion of the Approved Change Costs.&#160; Each Party may credit any
                      amounts paid under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.5(a)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.5(b)</u></font> against amounts
                      payable under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.5(c)</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For clarity, the allocation of Approved Change Costs set forth in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section









              3.1.5</u></font> will not apply to cost overruns associated with the Development Program that are not caused by Approved Changes.&#160; For example, activities to improve recruitment rate (<font style="font-size: 10pt; font-family: 'Times New
            Roman';"><u>e.g.</u></font>, adding additional sites (other than due to the addition of a new arm or due to an increase in the maximum number of study subjects, or the addition of sites such that the total number of sites exceeds [***]) or
          increasing site payments), recruitment vendors, or costs resulting from a delay in study conduct, are cost overruns associated with the Development Program and are not Approved Changes.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Approved Change Costs</font>&#8221;
          means [***] in each case with regard to clause (2) without considering the aggregate effect of all Approved Changes.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zb22707d7dba94c42afdb4757ec3276c7" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development Term</u></font>.&#160; The term for the conduct of the Development Program
                      under the Development Plan will begin on the date work began under such Development Plan and will end upon the earlier of (i) completion of all Development activities under such Development Plan to support Approval in at least one (1)
                      Indication in all Major Markets, (ii) the termination of such Development Program in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.1</u></font>, and (iii) mutual agreement of the
                      Parties to terminate the Development Program.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">5</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z0798b4518f1c4a51a40084318addd578" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Regulatory Matters</u></font>. Before Option exercise and until Completion of the
                      Proposed Phase 2 Trials, Ionis will be responsible for all communications with Regulatory Authorities regarding a Product and will have final decision-making authority with respect to the matters set forth in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zc282947858524b4b8c1122dd3deb5f85" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Participation in Regulatory Meetings</u></font>.&#160; Ionis will provide Roche with as
                      much advance written notice as practicable of any meetings that Ionis has or plans to have with a Regulatory Authority regarding the Proposed Phase 2 Trials and any other Phase 2 Trial or earlier stage Clinical Study that the Parties
                      agree Ionis will conduct for a Product and will allow Roche (at Roche&#8217;s own expense) to participate in any such meetings as an observer.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z2303c455c8e3428fa796609f47287632" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Regulatory Communications</u></font>.&#160; Ionis will provide Roche with copies of
                      documents and communications submitted to and received from Regulatory Authorities that materially impact the Development or Commercialization of a Product for Roche&#8217;s review and comment, and Ionis will consider in good faith
                      including any comments provided by Roche to such documents and communications.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 4.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">COLLABORATION GOVERNANCE; MANUFACTURING AND COSTS</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zfb103a8945f649249013da618567d3ec" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Collaboration Governance</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z6b260780d1344fb481600f99b5c7fa62" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Joint Steering Committee</u></font>. Within thirty (30) days after the Effective
                      Date, the Parties will establish a joint steering committee (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">JSC</font>&#8221;) to govern the activities under the Development Plan. The
                      JSC will consist of three (3) representatives appointed by Ionis and three (3) representatives appointed by Roche. Each Party&#8217;s JSC representatives will be senior personnel empowered by such Party to make decisions related to clinical
                      development and regulatory strategy, and at least one of each Party&#8217;s members will have operational responsibility for such Party&#8217;s respective activities under the Development Plan. Each Party will be responsible for the costs and
                      expenses of its own employees or consultants attending JSC meetings.&#160; The JSC will meet at least twice each Calendar Year but not more that four (4) times per Calendar Year. Ionis will have the right, but not the obligation, to
                      participate in the JSC after Option exercise.&#160; If Ionis chooses not to participate, then Roche can dissolve the JSC.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z75bdc5d99c1a48ea9636a937c54fc077" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Role of the JSC</u></font>. Without limiting any of the foregoing, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font>, the JSC will perform the following functions, some or all of which may be addressed directly at any given JSC meeting:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z2d0a86e7974141ec8650e5b4fead3176" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Review and approve updates to the Development Plan with respect to the Proposed Phase 2 Trials as well as with respect to any Phase 2 Trial undertaken per Section 3.1.3
                      (including any material changes) as contemplated under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1</u></font>;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">6</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z3d8da2f9ff884eb893018d298f547cb6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Review and approve regulatory filings regarding the Clinical Studies under the Development Plan with respect to the Proposed Phase 2 Trials as well as with respect to any
                      Phase 2 Trial undertaken per <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3</u></font> in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2</u></font>;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z1cc2f0d3da9a400f89f4ea66aef1d96b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Oversee the operation of any JDC regarding the Clinical Studies under the Development Plan with respect to the Proposed Phase 2 Trials as well as with respect to any
                      Phase 2 Trial undertaken per <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3</u></font>;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="ze5b392ce0b1c463690127a91982b7239" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iv)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Attempt to informally resolve any disputes that may arise between the Parties regarding the Proposed Phase 2 Trials as well as any Phase 2 Trial undertaken per <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3</u></font>; and</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zec88f5ed86e5428b8b331b707fae8cfd" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(v)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Such other review, approval and advisory responsibilities as may be assigned to the JSC by the Parties pursuant to this Agreement.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="za53ffa51025747fc985a5ad51a3450db" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Decision Making</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zc412812274fe47f8837cee81357eacc3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Committee Decision Making</u></font>. Decisions by the JSC will be made by unanimous
                      consent with each Party&#8217;s representatives having, collectively, one vote. At any given meeting of the JSC, a quorum will be deemed reached if a voting representative of each Party is present or participating in such meeting. No action
                      taken at any meeting of the JSC will be effective unless there is a quorum at such meeting. Unless otherwise specified in this Agreement, no action will be taken with respect to a matter for which the JSC has not reached unanimous
                      consensus.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z18f4080b75c749b0a0dad21b7bc79bd5" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Implementation</u></font>. Each Party will give due consideration to, and consider in
                      good faith, the recommendations and advice of the JSC regarding the conduct of the activities under the Development Plan. The JSC will endeavor in good faith to reach consensus on all decisions, <font style="font-size: 10pt;
                        font-family: 'Times New Roman'; font-style: italic;">however</font>, if the JSC cannot unanimously agree on a matter to be decided by it within fifteen (15) Business Days, then the matter may be referred to the Executives for
                      resolution as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.1.1</u></font>. If the Executives cannot reach agreement, then (i) before Option exercise, Ionis will have the final
                      decision-making authority regarding the performance of activities under the Development Plan and whether to accept and how to implement the JSC&#8217;s recommendations with respect thereto, and (ii) after Option exercise, Roche will have
                      the final decision-making authority regarding the performance of activities under the Development Plan and whether to accept and how to implement the JSC&#8217;s recommendations with respect thereto, except with respect to decisions
                      regarding operational aspects of a Phase 2 Trial conducted by Ionis that has not yet Completed, which will be within Ionis&#8217; final decision-making authority. In exercising its final decision-making authority under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)(ii)</u></font>, a Party will not increase the other Party&#8217;s costs or obligations under the Development Plan without such Party&#8217;s consent. Except as
                      otherwise expressly stated in this Agreement, the JSC will have no decision-making authority and will act as a forum for sharing information about the activities conducted by the Parties hereunder and as an advisory body, in each case
                      only on the matters described in, and to the extent set forth in, this Agreement.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">7</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z55912be69ae148adb3bafbf52e1cbb56" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Joint Development Committees</u></font>.&#160; Prior to the Initiation of the Phase 2 GA
                      Trial and the Phase 2 [***] Trial, as applicable, the Parties will establish a joint development committee (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">JDC</font>&#8221;) for the
                      Phase 2 GA Trial and a separate JDC for the Phase 2 [***] Trial.&#160; Thereafter, if the Parties agree that Ionis will conduct any other Phase 2 Trial under the Development Plan, within thirty (30) days after such agreement, the Parties
                      will establish a separate JDC for such Phase 2 Trial.&#160; Each JDC will consist of an equal number of representatives appointed by Ionis and Roche.&#160; Each Party will be responsible for the costs and expenses of its own employees or
                      consultants attending JDC meetings.&#160; Ionis will have the right, but not the obligation, to participate in each JDC after Option exercise.&#160; If Ionis chooses not to participate, then Roche can dissolve the JDC. Each JDC will be
                      dissolved as soon as reasonably possible after the Completion of the applicable ongoing Phase 2 Trial over which such JDC has oversight.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zd4831adc8de040ce83de86dd7b65f172" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Role of the JDCs</u></font>.&#160; Without limiting any of the foregoing, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2(b)</u></font>, the applicable JDC will perform the following functions, some or all of which may be addressed directly at any given JDC meeting:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zc468c66457a54a28bab67ad2904c73f6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">oversee the Parties&#8217; activities regarding the applicable Phase 2 Trial under the Development Plan;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7c5072a7b3bf4202b76da7c732d005e9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">oversee the formation and operation of any subcommittee of the JDC regarding the applicable Phase 2 Trial under the Development Plan;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z80fe12de66d34f6d96dc13c67dbb503b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">with respect to the JDC for the Phase 2 [***] Trial (or the JDC for any subsequent Phase 2 Trial that the Parties agree Ionis will conduct), discuss and agree upon the
                      proposed design and protocol(s) for the Phase 2 [***] Trial (or other Phase 2 Trial, if applicable) under the Development Plan and present such documents to the JSC for final approval; and</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z0a9b94e9cd6941e8a1d0fc27f90f22fd" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iv)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">such other review and advisory responsibilities as may be assigned to the applicable JDC by the Parties pursuant to this Agreement.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">8</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z4e3894644dcf459e9f7d808800b84d33" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Decision Making</u></font>.&#160; Decisions by the applicable JDC will be made by
                      unanimous consent with each Party&#8217;s representatives having, collectively, one vote.&#160; At any given meeting of the applicable JDC, a quorum will be deemed reached if a voting representative of each Party is present or participating in
                      such meeting.&#160; No action taken at any meeting of the applicable JDC will be effective unless there is a quorum at such meeting.&#160; Unless otherwise specified in this Agreement, no action will be taken with respect to a matter for which
                      the applicable JDC has not reached unanimous consensus.&#160; Each JDC will endeavor in good faith to reach consensus on all decisions over which it has oversight, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style:
                        italic;">however</font>, if a JDC cannot unanimously agree on a matter to be decided by it within fifteen (15) Business Days, then the matter will be referred to the JSC for resolution in accordance with <font style="font-size:
                        10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zcee4b4e3669e400480184901c2ef988d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Alliance Managers</u></font>. Each Party will appoint a representative to act as its
                      alliance manager under this Agreement (each, an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Alliance Manager</font>&#8221;). Each Alliance Manager will be responsible for supporting
                      the JSC and each JDC, and performing the activities listed in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New
                        Roman';"><u> 4.2</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z9523ff99658d45b086caf7c5ca4d4d24" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Records and Quality; Inspections; Materials Transfer</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z9e90d8a73b6f4ecf8ea729e187dd18d3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.3.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Records</u></font>. Each Party will maintain records consistent with its own practice
                      of all Development and Commercial activities such Party performs under this Agreement and all results, data, inventions and developments made in the performance of such work. Such records will be in sufficient detail and in good
                      scientific manner appropriate for compliance reporting, effective auditing, patent and regulatory purposes. Upon prior written notice, a Party will provide the other Party with copies of all requested records, to the extent reasonably
                      required for the performance of a Party&#8217;s rights and obligations under this Agreement.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z85167df24ab94fa594c2ea3866818d9c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.3.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Materials Transfer</u></font>. To facilitate the activities under this Agreement,
                      either Party may provide to the other Party certain materials for use by the other Party in furtherance of the activities to be performed under this Agreement. Unless agreed otherwise between the Parties, all such materials will be
                      used by the receiving Party in accordance with the terms and conditions of this Agreement solely for purposes of exercising its rights and performing its obligations under this Agreement, and the receiving Party will not transfer such
                      materials to any Third Party unless expressly contemplated by this Agreement or upon the written consent of the supplying Party. Except as expressly set forth herein, SUCH 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>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">9</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div><br>
            </div>
            <div>
              <div style="text-align: justify;">
                <div>
                  <table cellspacing="0" cellpadding="0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                      <tr>
                        <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.4.</font></td>
                        <td style="width: auto; vertical-align: top; text-align: justify;">
                          <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Manufacturing and Supply</u></font>. Unless otherwise expressly agreed by the
                              JSC:</font></div>
                        </td>
                      </tr>

                  </table>
                </div>
              </div>
            </div>
            <br>
          </div>
          <table cellspacing="0" cellpadding="0" id="zcf015e89825d49e6ac713a9a3304a9be" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.4.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Supplies for Activities Before Option Exercise</u></font>.&#160; Ionis is solely
                      responsible for the manufacture and supply of API and Finished Drug Product to support the activities under the Development Plan through Completion of the Proposed Phase 2 Trials, including any costs associated with such manufacture
                      and supply.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z6102d831f5a347a6a9947ed821b95744" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.4.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Supplies for Activities After Option Exercise</u></font>.&#160; After Option exercise,
                      Ionis will deliver to Roche, if Roche desires, any inventory of cGMP and non-cGMP API, cGMP and non-cGMP Finished Drug Product, and cGMP and non-cGMP packaged clinical trial material containing IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in Ionis&#8217; possession and that is not necessary to complete any then ongoing Phase 2 Trials being conducted by Ionis under the Development Plan [***] as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.4.2</u></font>.&#160; After Option exercise, Roche is
                      responsible for the manufacture and supply of API and Finished Drug Product to support the activities under the Development Plan (except for any then-ongoing additional Phase 2 Trial being conducted by Ionis and any then-ongoing
                      Proposed Phase 2 Trials) and to Commercialize Product, including any costs associated with such manufacture and supply, and Ionis will, at Roche&#8217;s election either (i) assign to Roche contracts Ionis has with Third Party manufacturers
                      for the manufacture of such API or Finished Drug Product and will use commercially reasonable efforts to support Roche in qualifying such Third Party manufacturers, or (ii) transfer to Roche the Ionis Manufacturing and Analytical
                      Know-How in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.2</u></font>, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.3</u></font>.&#160; If,
                      prior to Option exercise, Roche elects to perform preliminary chemistry, manufacturing and controls work to evaluate the feasibility of manufacturing the Product or to determine whether to pursue either of the foregoing options
                      specified in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.4.2</u></font>, Ionis will cooperate in good faith with Roche and will provide the materials and information requested by Roche necessary
                      to such evaluation. Each Party shall bear its own costs for such activities pursuant to the preceeding sentence.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7f6a7df6219d49909b83ffa1768fdcdb" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Subcontracting</u></font>.&#160; Each Party may engage Third Party subcontractors to
                      perform certain of its obligations under this Agreement.&#160; 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.&#160; Any Party engaging a subcontractor hereunder will remain responsible for such activities.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z6fcd3e6f07f8452d87743a5303408c1b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Applicable Laws</u></font>.&#160; Each Party will perform its activities pursuant to this
                      Agreement in compliance with Applicable Law, including good laboratory and clinical practices and cGMP, in each case as applicable in the country, state, province, territory, and locale wherein such activities are conducted.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">10</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: left;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
        </font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 5.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">EXCLUSIVITY COVENANTS</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z26e6ded1ab624d2e9d6cc7d9adfbe7c1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Exclusivity Covenants</u></font>.&#160; 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1.3</u></font>:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z74f0fa13e3844adea6ae9ec0b5a8ce21" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Before Option Exercise</u></font>.&#160; Before Option exercise, Ionis 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 Factor B in the Field.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z2c629b10fb424820a07c10aae3e80738" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>After Option Exercise</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z22c16c036d3f4e65aa840b0107f6aa50" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">After Option exercise, if Roche is Developing or Commercializing at least one Product under this Agreement, neither Ionis nor Roche independently or for or with any of
                      their respective Affiliates or any Third Party (including the grant of any license to any Third Party) will sell an ASO approved by a Regulatory Authority for marketing and sale that is designed to bind to the RNA that encodes Factor
                      B in the Field&#160; until the Full Royalty Period ends in the first Major Market. After the end of the Full Royalty Period in the first Major Market, the exclusivity covenants set forth in this <font style="font-size: 10pt; font-family:
                        'Times New Roman';"><u>Section 5.1.2(a)</u></font> will continue on a country-by-country basis in each country where the Full Royalty Period still applies [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z69bd9881924d4f4da9b9bdbbeedafb81" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The exclusivity covenants of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1.2(a)</u></font> will not apply to [***] or [***], <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that </font>Roche [***], or otherwise [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z355a60b9d17e441e9b174b71b0402dfe" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Limitations and Exceptions to </u></font><font style="font-size: 10pt; font-family:
                        'Times New Roman'; font-weight: bold;"><u>Ionis</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>&#8217; and Roche&#8217;s Exclusivity Covenants</u></font><font style="font-size: 10pt; font-family:
                        'Times New Roman';">.</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>Notwithstanding anything to the contrary in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section









                          5.1</u></font>, the Parties and their Affiliates may perform the following activities:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z9a23d55deb0242e9af671f65d7c95763" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">all activities permitted or contemplated under this Agreement; and</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7d066183b0c84bfbba84111046ef76eb" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">with regard to Ionis and its Affiliates:</font></div>
                </td>
              </tr>

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        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z6a96ebe6f6d8440fa47c1a5f7ca4b616" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any activities pursuant to the Prior Agreement;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z5cc589a213364534aa9a0cfed7f1d1ce" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the granting of, or performance of obligations under, Permitted Licenses.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="ze67ac7f76e434620b72bc031a5ab2ee5" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Effect of Exclusivity on Indications</u></font>. Ionis and Roche are subject to
                      certain exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font>; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">however</font>, the
                      Parties acknowledge and agree that each Party (on its own or with a Third Party, or an Affiliate) may pursue products for the same Indication as a Product so long as such product is <font style="font-size: 10pt; font-family: 'Times
                        New Roman';">not an ASO designed to bind to the RNA that encodes Factor B</font>.</font></div>
                </td>
              </tr>

          </table>
          <div> <br>
          </div>
        </div>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">11</font></div>
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      <div style="text-align: left;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
        </font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 6.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">EXCLUSIVE OPTION</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zb5b0d4e28e8546f790c439ad6d1e04db" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Option and Option Deadline</u></font>.&#160; Ionis hereby grants Roche an exclusive option
                      to obtain the license set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font> (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option</font>&#8221;).&#160;









                      To obtain the license set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>, Roche must exercise the Option by the [***] following Roche&#8217;s receipt of the Phase 2 Trial Data Package
                      from Ionis (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Deadline</font>&#8221;).&#160; If, however, the Phase 2 GA Trial [***] and Roche is conducting the Phase 2b [***] Trial
                      under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3(c)</u></font> or Ionis is conducting an additional Phase 2 Trial or any additional earlier stage Clinical Study for the Product under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3(a)</u></font>, then the Option Deadline will be extended until [***] after the Completion of the Phase 2b [***] Trial.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z15fa47165f0d4b27a2f78ea64d211aad" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Option Exercise; Option Expiration</u></font>.&#160; During the Option Period, if, by the
                      Option Deadline, Roche (i) notifies Ionis in writing that it is exercising the Option (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Exercise Notification</font>&#8221;), and
                      (ii) within [***] after the latest of (x) the Option Exercise Notification, (y) Roche&#8217;s receipt of an invoice from Ionis, and (z) expiration or termination of any applicable waiting period under the HSR Act or any other similar
                      Applicable Law, Roche timely pays Ionis the license fee set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.3</u></font>, Ionis will, and hereby does, grant Roche the license set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>.&#160; Prior to the Option Deadline, Roche will have the full opportunity to conduct due diligence to evaluate whether to exercise the Option and Ionis
                      will cooperate with Roche and ensure that all necessary data and information, including clinical and manufacturing data and any available [***] analysis, are provided to Roche.&#160; If, by the Option Deadline, Roche has not provided Ionis
                      the Option Exercise Notification, and within [***] after the latest of (1) providing the Option Exercise Notification, (2) receiving an invoice from Ionis for the license fee set forth in <font style="font-size: 10pt; font-family:
                        'Times New Roman';"><u>Section 9.3,</u></font> and (3) expiration or termination of any applicable waiting period under the HSR Act or any other similar Applicable Law, has not paid Ionis the license fee set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.3</u></font>, then Roche&#8217;s Option will expire.&#160; If Roche&#8217;s Option expires, then <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.1</u></font>
                      and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.2</u></font> will apply.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z14666c8d18784cd487411a617aefdd01" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>HSR</u></font>.&#160; Each Party will (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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2</u></font>.&#160; Each Party will 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 will 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2</u></font> of this Agreement, should Roche choose to exercise the Option.&#160; Notwithstanding anything to the
                      contrary contained in this Agreement, Roche will have the sole and exclusive right to determine, at its discretion but without any obligation whatsoever, whether it will 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 Ionis, 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>
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          </table>
        </div>
      </div>
      <div><br>
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      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">12</font></div>
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      <div style="text-align: left;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
        </font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 7.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">LICENSE GRANTS</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z95e36c9f376d4a4a8cd82609a5175884" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>License Grants; Sublicense Rights</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="za4415b8998884849a49e1d1b3a9693da" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development and Commercialization License Grant to Roche</u></font>. Subject to the
                      terms of this Agreement, effective upon Roche&#8217;s exercise of the Option in accordance with this Agreement, Ionis grants to Roche a worldwide, exclusive, royalty-bearing, sublicensable (in accordance with <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 7.1.4</u></font> below) license under the Licensed Intellectual Property to Develop, Manufacture, have Manufactured (in accordance with <font style="font-size: 10pt; font-family: 'Times
                        New Roman';"><u>Section 7.1.4</u></font> below), use, and Commercialize Products in the Field.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z3f398cee13fb406aac57afba996f387e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Cross Licenses under Collaboration Intellectual Property</u></font>.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z1addf22d34df4a55a29fa1a76683b1a3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Enabling Patent License from Roche to Ionis</u></font>. Subject to the terms and
                      conditions of this Agreement (including Ionis&#8217; exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font> and without limiting the license granted to Roche under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>), Roche hereby grants Ionis a fully-paid, royalty-free, irrevocable, worldwide, non-exclusive, sublicensable license under any Roche Collaboration
                      Intellectual Property (excluding any Product-Specific Patents) to research, develop, manufacture, have manufactured and commercialize products that include an ASO as an active pharmaceutical ingredient (other than a Product that is
                      being Developed or Commercialized by Roche, its Affiliates or Sublicensees under this Agreement or the HTT Research, Development, Option and License Agreement among the Parties dated April 8, 2013).</font></div>
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        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7f2c64f410d24ba481993edd6152a4f9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Enabling Patent License from Ionis to Roche</u></font>. Subject to the terms and
                      conditions of this Agreement (including Roche&#8217;s exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font> and without limiting the license granted to Roche under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>), Ionis hereby grants Roche a fully-paid, royalty-free, irrevocable, worldwide, non-exclusive, sublicensable license under any Ionis Collaboration
                      Intellectual Property (excluding any Ionis Product-Specific Patents) to research, develop, manufacture, have manufactured and commercialize products that do not include an ASO as an active pharmaceutical ingredient.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zf219ff13893f4d588bdd7f9c71b5ae8c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Amendment to the Existing Diagnostic Agreement</u></font>.&#160; After Option exercise,
                      Ionis and Roche will execute an amendment to the Existing Diagnostic Agreement on terms mutually agreed by Roche and Ionis, 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 Ionis necessary or useful to research, develop , manufacture, have manufactured, and commercialize Factor B diagnostic products (including
                      diagnostic products and/or services to select patients who will use Products).</font></div>
                </td>
              </tr>

          </table>
          <div> <br>
          </div>
        </div>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">13</font></div>
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        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z5e757f04def54110b10b7212944dc37e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Sublicense Rights</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zb1147087de2b429e9a012d62678e0ef4" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the terms of this Agreement, Roche will have the right to grant sublicenses under any license granted under <font style="font-size: 10pt; font-family: 'Times
                        New Roman';"><u>Section 7.1.1</u></font> above:</font></div>
                </td>
              </tr>

          </table>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7ec66f042724484d9753a70c9b213d60" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">under Ionis&#8217; interest in Jointly Owned Collaboration IP to the extent it is exclusively licensed to Roche under this Agreement, the Ionis Core Technology Patents, Ionis
                      Product-Specific Patents, Ionis Collaboration Patents, Ionis Collaboration Know-How, and Ionis Know-How to an Affiliate of Roche or a Third Party; and</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z80e664fbb28642879946df017974fb17" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">under the Ionis Manufacturing and Analytical Patents and Ionis Manufacturing and Analytical Know-How solely to (y) an Affiliate of Roche or (z) a [***] (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Licensed CMO</font>&#8221;).</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z62f967c88dee413896016c824d91afa6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Requests to Grant Sublicenses to CMOs</u></font>. If Roche provides Ionis with a
                      written request that Ionis grant a license under the Ionis Manufacturing and Analytical Patents and Ionis 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></div>
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          </table>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z675d6b1567cd42018e9be32b50287766" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Enforcing Sublicenses</u></font>. Each sublicense by Roche under this Agreement will
                      be subject to, and consistent with, the terms of this Agreement.&#160; Roche will be responsible to ensure compliance by its Sublicensees with the terms and conditions of this Agreement. If Ionis reasonably believes a Roche Sublicensee may
                      be violating the terms of this Agreement, then, within thirty (30) days after Ionis delivers a written request to Roche, Roche will provide Ionis a full and complete copy of the sublicense Roche entered with such Sublicensee.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z5e50813feb07414cb0b3c43daec5a082" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Effect of Termination on Sublicenses</u></font>. 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 Ionis with respect to the rights sublicensed to
                      the Sublicensee by Roche; <font style="font-size: 10pt; font-family: 'Times New Roman'; 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 Ionis 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 Ionis and if requested, the Sublicensee.</font></div>
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          </table>
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      </div>
      <div><br>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">14</font></div>
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        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z0f86c240452c4af8b2e3e9207838caba" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>No Implied Licenses</u></font>. All rights in and to Licensed Intellectual Property
                      not expressly licensed to Roche under this Agreement are hereby retained by Ionis or its Affiliates. All rights in and to Roche Intellectual Property not expressly licensed or assigned to Ionis 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>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="za724b6f0242f4379949e42fccd063b52" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>License Conditions; Limitations</u></font>. Subject to <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 9.10</u></font>, any license granted under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font> and the sublicense rights under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.4</u></font> is subject to and limited by (i) the Permitted Licenses, (ii) the Prior Agreement, and (iii), if any, the Additional Ionis 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z63ea46a7888b45aeba1470698196a768" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.7.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Trademarks for Products</u></font>. 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z8eed744ef83a4063b68962198276796b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Technology Transfer after Option Exercise</u></font>. After Option exercise pursuant
                      to a technology transfer plan to be mutually agreed by Ionis and Roche, and subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.3</u></font>, Ionis will:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z880c8d0559104ab28f7028cc0d5ab7d4" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.2.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Licensed Know-How &#8211; Generally</u></font>. Deliver to Roche copies of Licensed
                      Know-How (other than the Ionis Manufacturing and Analytical Know-How) in the Field in Ionis&#8217; possession not previously provided hereunder, for use solely in accordance with the license granted under <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 7.1.1</u></font> to Roche, together with all regulatory documentation (including drafts) related to any Phase 2 Trial Completed as of Option exercise. Following Option exercise, the
                      Parties will promptly agree on a plan to transfer to Roche (i) all regulatory documentation (including drafts) related to any Phase 2 Trial in progress as of Option exercise following the Completion of such Phase 2 Trial and (ii) any
                      other regulatory documentation regarding the Product in Ionis&#8217; possession not previously provided to Roche.&#160; To assist with the transfer of such Licensed Know-How, Ionis will make its personnel reasonably available to Roche during
                      normal business hours to transfer such Licensed Know-How under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.1</u></font>.</font></div>
                </td>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z828be5e3501a4b9f91f0fdc455ab92a7" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.2.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis Manufacturing and Analytical Know-How</u></font>. Deliver, at Roche&#8217;s election,
                      to one of either (i) Roche or (ii) a Licensed CMO solely to Manufacture API and Finished Drug Product on Roche&#8217;s behalf, copies of the Ionis Manufacturing and Analytical Know-How relating to Products in Ionis&#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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">15</font></div>
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential<br>
              <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="zda29c565898343ee9d0c9394d1206acf" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.2.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Technology Transfer Costs</u></font>. Perform the technology transfer activities
                      under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2</u></font> for up to [***] FTE hours (free of charge to Roche) of Ionis&#8217; time. Thereafter, if requested by Roche, Ionis will provide Roche with
                      a reasonable level of assistance in connection with such transfer, which Roche will reimburse Ionis for Ionis&#8217; time incurred in providing such assistance at Ionis&#8217; then-current FTE rate, and any of Ionis&#8217; reasonable travel expenses
                      for travel requested by Roche, and any outside consultants&#8217; costs and consultants&#8217; reasonable travel expenses incurred by Ionis agreed in advance by Roche.</font></div>
                </td>
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          </table>
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      </div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 8.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zd779747f88c14ac2afd1a5ec51a39cb1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Roche Diligence</u></font>.&#160; 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 the
                      Products, except with respect to any Phase 2 Trial being conducted by Ionis under the Development Plan that has not yet Completed by the time of Option exercise, which will remain the responsibility of Ionis until such Phase 2 Trial
                      has Completed.&#160; Roche will use Commercially Reasonable Efforts to Develop, Manufacture and Commercialize Products, including to meet the timelines and milestones set forth in the Development Plan, the IDCP and the Specific Performance
                      Milestone Events.</font></div>
                </td>
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          </table>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z85f8b16225df423a949d94fd3262a23c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Replacement of Development Plan with the IDCP</u></font>.&#160; Prior to Initiation of the
                      first Registration-Directed Trial for a given Product, Roche will prepare a global integrated development and commercialization plan (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style:
                        italic;">IDCP</font>&#8221;) outlining key aspects for Developing such Product through Approval of at least one (1) Indication, and Roche&#8217;s worldwide strategy to launch and Commercialize such Product.&#160; The IDCP will incorporate and
                      replace the Development 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.&#160; Once Roche has prepared such plan, Roche will update the IDCP consistent with Roche&#8217;s standard practice and provide such updates to Ionis at least Annually.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zde08b5a4396f485ca4a24016fb07c2c1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Registration-Directed Trials</u></font>. The Registration-Directed Trials will be
                      designed in accordance with the Registration-Directed Trial designs set forth in the applicable IDCP.&#160; Roche will keep Ionis informed of the progress and status of each Registration-Directed Trial.&#160; Roche will notify Ionis in writing
                      promptly after Roche completes each Registration-Directed Trial under the applicable IDCP.&#160; Once the data generated under the statistical analysis plan for a Registration-Directed Trial is available to Roche, Roche will provide
                      promptly such data to Ionis.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7e614a4022934f7290433e6c6b8cceac" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Investigator&#8217;s Brochure</u></font>.&#160; After Option exercise, in addition to the IDCP,
                      Roche will keep Ionis 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 Ionis Annually and upon any substantive change to
                      the safety or risk of the Products.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">16</font></div>
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
          </div>
          <div> <br>
          </div>
          <table cellspacing="0" cellpadding="0" id="z7eb2e20e843a4aa89b17b1f353a4f504" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Participation in Regulatory Meetings</u></font>.&#160; 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. After Option exercise and upon transfer of the IND for IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to
                      Roche, Roche will lead all interactions with Regulatory Authorities regarding IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and Products.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zef2d82fe3ec74b44918e39aa441781a9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Regulatory Communications</u></font>.&#160; 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="ze2289330789d494da31182db80e653a3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Participation in Roche Clinical Development Team Meetings</u></font>.&#160; [***], Roche
                      will permit Ionis to participate in Roche&#8217;s key clinical development team meetings for Products (<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">i.e.</font>, meetings that are likely to have a
                      material impact on the Development of the Product(s) (each such meeting, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Key Meeting</font>&#8221;), at Ionis&#8217; reasonable request.&#160;
                      Ionis&#8217; and Roche&#8217;s respective designated clinical leaders will work together to come up with a schedule of such Key Meetings, giving Ionis as much advance written notice as practicable so that Ionis may, at Ionis&#8217; expense, plan for
                      its participation in such meetings.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z3a345987795b474982a1d935d0753731" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.7.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Class Generic Claims</u></font>.&#160; If Roche intends to make any claims in a Product
                      label or regulatory filing that are class generic to ASOs or Ionis&#8217; chemistry platform(s), Roche will provide such claims and regulatory filings to Ionis in advance and will consider in good faith any proposals and comments made by
                      Ionis.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z3809eed6924447c7b875bdb971a7aecc" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>IND; Global Safety Database</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z82d7c459f0fd455286d9b60868aef8e2" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Transfer of the IONIS-FB-L</u></font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold;"><u>Rx</u></font></sub><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u> IND to Roche; Global Safety Database Responsibilities</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">.</font> Until the Completion of the Proposed Phase 2 Trials and any other Phase 2 Trial conducted by Ionis under the Development Plan, Ionis will be the
                      holder of the IND for IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>. After Option exercise and upon Completion of the Proposed Phase 2 Trials and any other Phase 2 Trial conducted by Ionis
                      under the Development Plan, Ionis will transfer promptly the IND to Roche. Upon transfer of the IND to Roche and assumption by Roche of regulatory responsibilities under the IND, Roche will assume responsibility for the global safety
                      database related to IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx </sub>and 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 IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> and will furnish copies of such reports to Ionis.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">17</font></div>
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
          </div>
          <div> <br>
          </div>
          <table cellspacing="0" cellpadding="0" id="zb203a71ff1d94d4da9238ca730d4ab1b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Antisense Safety Database</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z68926e0eb88647d48febf2d67374f518" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis maintains an internal database that includes information regarding the tolerability of its drug compounds, individually and as a class, including information
                      discovered during non-clinical and clinical development and commercialization (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Internal ASO Safety Database</font>&#8221;). The
                      Ionis Internal ASO Safety Database is an internal database owned and maintained by Ionis to maximize Ionis&#8217; and its partners&#8217; understanding of Ionis&#8217; compounds, and it is separate from, and not a substitute for, the global safety
                      database for which Roche will be responsible under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.2.1</u></font> above. To maximize understanding of the safety profile and pharmacokinetics of Ionis
                      compounds, after Option exercise, Roche will cooperate in connection with populating the Ionis 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 Ionis 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 Ionis starting no later than thirty (30) days after Roche&#8217;s receipt of such information). In connection with any reported serious
                      adverse event for a Product, Roche will provide Ionis 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 Ionis
                      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 Ionis any supporting data and answer any follow-up questions reasonably requested by Ionis. All such information disclosed by Roche to Ionis will be Roche Confidential Information; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Ionis may disclose any such Roche Confidential Information to (i) Ionis&#8217; other partners pursuant to <font style="font-size:
                        10pt; font-family: 'Times New Roman';"><u>Section 8.2.2(b)</u></font> below if such information is regarding class generic properties of ASOs, or (ii) any Third Party, in each case, so long as Ionis does not disclose the identity of
                      a Product or Roche. Roche will contact Ionis&#8217; Chief Medical Officer at Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, California 92010 (or at such other address/contact designated in writing by Ionis) for matters related
                      to the Ionis Internal ASO Safety Database. Roche will also cause its Affiliates and Sublicensees to comply with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.2.2(a)</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z27ee390dab3445dc9b1bb8eb1951641d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis utilizes the information in the Ionis Internal ASO Safety Database to conduct analyses to keep Ionis and its partners informed regarding class generic properties of
                      ASOs, including with respect to safety. As such, if and when Ionis identifies safety or other related issues that may be relevant to a Product (including any potential class-related toxicity), Ionis will promptly inform Roche of such
                      issues and, if requested, provide the data supporting Ionis&#8217; conclusions.</font></div>
                </td>
              </tr>

          </table>
          <div> <br>
          </div>
        </div>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">18</font></div>
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      </div>
      <div style="text-align: left;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"> <br>
      </font>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">ARTICLE 9.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">FINANCIAL PROVISIONS</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
        </font></div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z9b6a0e8b01b44e08afcc82d6f8b13cca" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Option Fee</u></font>.&#160; 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 Ionis, Roche will pay Ionis an option fee of seventy-five million dollars (US$75,000,000).</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z78fbfbe0ab774e21a7118ffe3f772327" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Pre-Option Development Milestone</u></font>.&#160; In partial consideration for Roche&#8217;s
                      Option hereunder, Roche will pay Ionis a pre-option development milestone of [***] (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Option Development Milestone Payment</font>&#8221;),









                      which will be payable within [***] days after Roche receives from Ionis written notice that [***] (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Option Development
                        Milestone Event</font>&#8221;) and receipt by Roche of an invoice in such amount from Ionis.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z52ef8f2adb5940e694e4ef3777b108e0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>License Fee</u></font>.&#160; Pursuant to <font style="font-size: 10pt; font-family:
                        'Times New Roman';"><u>Section 6.2</u></font>, subsequent to Roche&#8217;s Option Exercise Notification, Roche will pay to Ionis a license fee of [***] within the timelines set forth in <font style="font-size: 10pt; font-family: 'Times
                        New Roman';"><u>Section 6.2</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z67182a0ff7154758b293446bd4cb22e6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Milestone Payments for Achievement of Post-Licensing Milestone Events</u></font>. As
                      further consideration for the licenses granted herein, Roche will pay to Ionis the applicable one-time milestone payments set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table
                          1</u></font> below (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Post-Licensing Milestone Payment</font>&#8221;) when the corresponding milestone event listed in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 1</u></font> (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Post-Licensing
                        Milestone Event</font>&#8221;) is first achieved by a Product for the specified Indication:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" border="0" id="zcd6a633404da4de483c4756c70112bd6" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;">

          <tr>
            <td style="width: 1%; vertical-align: middle; background-color: rgb(191, 191, 191); border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="vertical-align: middle; background-color: rgb(191, 191, 191); border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="3">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Table 1</u></font></font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; background-color: rgb(217, 217, 217); border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 33%; vertical-align: middle; background-color: rgb(217, 217, 217); border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Post-Licensing Milestone</font></div>
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Event</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; background-color: rgb(217, 217, 217); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Post-Licensing Milestone</font></div>
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Payment &#8211; Non-Rare</font></div>
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Disease Indication</font></div>
            </td>
            <td style="width: 33%; vertical-align: top; background-color: rgb(217, 217, 217); border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Post-Licensing Milestone</font></div>
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Payment &#8211; Second Indication</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 33%; vertical-align: middle; border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Total Post-Licensing Milestone Payments</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-bottom: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
            </td>
            <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
            </td>
          </tr>

      </table>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">19</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z2ef17755cae14e5b908eab1ca8afff2e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Milestone Payments for First Achievement of Sales Milestone Event</u></font>. Roche
                      will pay Ionis the applicable one-time milestone payments set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table</u></font><font style="font-size: 10pt; font-family: 'Times New
                        Roman';"><u> 2</u></font> below (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Sales Milestone Payment</font>&#8221;) after the first achievement of the corresponding event
                      listed in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 2</u></font> (each, a &#8220;<font style="font-size:
                        10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Sales Milestone Event</font>&#8221;), by or on behalf of Roche or its Affiliates or Sublicensees.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <table cellspacing="0" cellpadding="0" border="0" align="center" id="z44e16aebeee54016bc5005715dd16e26" style="border-collapse: collapse; width: 60%; font-family: 'Times New Roman'; font-size: 10pt;">

          <tr>
            <td style="vertical-align: middle; background-color: rgb(204, 204, 204); border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); width: 1%;" colspan="1">&#160;</td>
            <td style="vertical-align: middle; background-color: rgb(204, 204, 204); border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="2">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Table 2</u></font></font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; background-color: rgb(217, 217, 217); border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 39%; vertical-align: middle; background-color: rgb(217, 217, 217); border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Sales Milestone Event</font></div>
            </td>
            <td style="width: 20%; vertical-align: top; background-color: rgb(217, 217, 217); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Sales Milestone</font></div>
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Payment</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 39%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***] in worldwide Annual Net Sales of a Product</font></div>
            </td>
            <td style="width: 20%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 39%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***] in worldwide Annual Net Sales of a Product</font></div>
            </td>
            <td style="width: 20%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 39%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***] in worldwide Annual Net Sales of a Product</font></div>
            </td>
            <td style="width: 20%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 1%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 39%; vertical-align: middle; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Total Sales Milestone Payments</font></div>
            </td>
            <td style="width: 20%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
            </td>
          </tr>

      </table>
      <div style="text-align: justify;">
        <div>
          <div> <br>
          </div>
          <table cellspacing="0" cellpadding="0" id="zaf71c9157a7047c7989e9c3c163e9c19" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Limitations on Milestone Payments; Exceptions; Notice</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z0c0e51b656394125a30452aa5938ff92" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.6.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Each milestone payment set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 1</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 2</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;">&#160;</font>above will be paid only once
                      upon the first achievement of the applicable Milestone Event, regardless of the number of Products subsequently achieving such Milestone Event or the number of times a given Product reaches such Milestone Event.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z80b4a95682cc442a9dff64d8c8be5823" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.6.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If a particular Post-Licensing Milestone Event is not achieved because regulatory activities transpired such that achievement of such earlier Post-Licensing Milestone
                      Event was unnecessary or did not otherwise occur, then upon achievement of a later Post-Licensing Milestone Event the Post-Licensing Milestone Payment applicable to such earlier Post-Licensing Milestone Event will also be due.&#160; For
                      example, if Roche proceeds directly to [***] without achieving the [***], then upon achieving the [***] Milestone Event, both the [***] and [***] Post-Licensing Milestone Payments will be due. For clarity, [***] or [***] in one region
                      does not trigger milestone payments in other regions.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z9cfb30330f2240a1b821892ef438d9a3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
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                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.6.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If a particular Milestone Event is achieved contemporaneously with or in connection with another Milestone Event, then both Milestone Events will be deemed achieved and
                      the milestone payments for both Milestone Events will be due.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zc8f96fc968ab42c58c054e12f7f17862" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.6.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Each time a Milestone Event is achieved under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.4</u></font> or <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 9.5</u></font>, Roche will send to Ionis 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 after the date such Milestone Event was achieved and receipt of an invoice by Roche from Ionis.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">20</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z46342b9dd54f4ef48c19fca6ddb32191" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.7.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Royalty Payments to Ionis</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z4c36000c154e424d97c9ba1b8635341c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.7.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Roche Full Royalty</u></font>. As partial consideration for the rights granted to
                      Roche hereunder, subject to the provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.1</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2</u></font>,
                      Roche will pay to Ionis royalties on worldwide Annual 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-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 3</u></font> below (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche Full
                        Royalty</font>&#8221;):</font></div>
                </td>
              </tr>

          </table>
          <div> <br>
          </div>
        </div>
      </div>
      <table cellspacing="0" cellpadding="0" border="0" align="center" id="zacd7e9b72bbb40c2a6d107ee3f670d28" style="border-collapse: collapse; width: 70%; font-family: &quot;Times New Roman&quot;; font-size: 10pt;">

          <tr>
            <td style="background-color: #BFBFBF; border-left: 2px solid; border-top: 2px solid #000000; vertical-align: top; width: 10%;" rowspan="1">&#160;</td>
            <td style="background-color: #BFBFBF; border-left: 2px solid; border-top: 2px solid #000000; vertical-align: middle; width: 1%;" colspan="1" rowspan="1">&#160;</td>
            <td style="background-color: #BFBFBF; border-top: 2px solid #000000; vertical-align: middle; width: 49%;" rowspan="1">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Table 3</u></font></font></div>
            </td>
            <td style="background-color: #BFBFBF; border-left: 2px solid; border-right: 2px solid; border-top: 2px solid #000000; vertical-align: middle; width: 10%;" rowspan="1">&#160;</td>
          </tr>
          <tr>
            <td style="width: 10%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Royalty</font></div>
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Tier</font></div>
            </td>
            <td style="width: 1%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 49%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Worldwide Annual Net Sales of Products</font></div>
            </td>
            <td style="width: 10%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Royalty</font></div>
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Rate</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 10%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">1</font></div>
            </td>
            <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 49%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For the portion of worldwide Annual Net Sales &lt; US$[***]</font></div>
            </td>
            <td style="width: 10%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]%</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 10%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">2</font></div>
            </td>
            <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 49%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For the portion of worldwide Annual Net Sales <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>&gt;</u></font> US$[***] but &lt;
                  US$[***]</font></div>
            </td>
            <td style="width: 10%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]%</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 10%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">3</font></div>
            </td>
            <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 49%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For the portion of worldwide Annual Net Sales <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>&gt;</u></font> US$[***] but &lt;
                  US$[***]</font></div>
            </td>
            <td style="width: 10%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]%</font></div>
            </td>
          </tr>
          <tr>
            <td style="width: 10%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">4</font></div>
            </td>
            <td style="width: 1%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);" colspan="1">&#160;</td>
            <td style="width: 49%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For the portion of worldwide Annual Net Sales <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>&gt;</u></font> US$[***]</font></div>
            </td>
            <td style="width: 10%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]%</font></div>
            </td>
          </tr>

      </table>
      <div style="text-align: justify;">
        <div>
          <div> <br>
          </div>
          <table cellspacing="0" cellpadding="0" id="zc1db94a6c4d841a889e2ba26d7db82a9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">For purposes of <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 3</u></font>, Worldwide Annual Net Sales for a
                      particular Product will be calculated by [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z515c6f15871140349e4213087b334dad" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Roche will pay Ionis 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 Ionis consistent with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.11</u></font>. 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="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font></font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zee11fbe007b545bfafbcf3a0e76bdb50" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.7.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Application of Royalty Rates</u></font>. All royalties set forth under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.1</u></font> are subject to the provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2</u></font>, and are payable
                      as follows:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7393835e424d4f1eabc47611a89ba482" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Full Royalty Period</u></font>. Roche&#8217;s obligation to pay Ionis 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 latest of (i) the date of expiration of the last Valid Claim
                      within the Licensed Patents Covering such Product in the country in which such Product is used or sold, (ii) the date of expiration of the data exclusivity period conferred by the applicable Regulatory Authority in such country with
                      respect to such Product (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>, such as in the case of an orphan drug), or (iii) the [***] anniversary of the First Commercial Sale of such Product in such
                      country <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>unless</u></font> a [***] in such country, at which time in lieu of paying the Roche Full Royalty, Roche will pay Ionis the Roche Reduced
                      Royalty for such Product in such country in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2(b)</u></font> (such royalty period, the &#8220;<font style="font-size: 10pt; font-family: 'Times
                        New Roman'; font-weight: bold; font-style: italic;">Full Royalty Period</font>&#8221;).&#160; For clarity, (X) Licensed Patents that are Jointly-Owned Collaboration Patents, and (Y) Roche Collaboration Patents, 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 Jointly-Owned Collaboration Patent or Roche
                      Collaboration Patent.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">21</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z971e4d6afc5d41668e4de7422908964f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Reduced Royalty Period</u></font>. Subject to <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 9.7.2(c)</u></font>, 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-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 3</u></font> of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.1</u></font>,
                      Roche will pay Ionis royalty rates (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>[***]</u></font>; <font style="font-size: 10pt; font-family: 'Times New Roman'; 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7</u></font>. For
                      example, if peak Calendar Year Net Sales of Products during the Full Royalty Period were US$[***] and royalties paid for that same Calendar Year were US$[***] resulting in a [***], and if [***] and the [***], the applicable [***] in
                      such country would be [***]. Similarly, if the [***], then the applicable [***] in such country would be [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 108pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Notwithstanding anything to the contrary in this subsection (b), if, during the Reduced Royalty Period for a Product, Ionis (on its
          own or with a Third Party) following marketing approval sells an ASO designed to bind to the RNA that encodes Factor B in the Field, then such Reduced Royalty Period will end and Roche&#8217;s worldwide license under <font style="font-size: 10pt;
            font-family: 'Times New Roman';"><u>Section 7.1.1</u></font> solely with respect to such Product will become fully paid-up and royalty-free.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z0e421906708944bf948cc713fb2c09bd" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Limitation on Aggregate Reduction for Roche Royalties</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z2edceefec3db4c4c8479622ccaefb4a4" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In no event will the royalty reductions under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2(b)</u></font> reduce the royalties payable
                      to Ionis on Net Sales of the applicable Product in any given period to an amount that is less than the [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z255970024b694cf38e8f01b902f8e284" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In no event will the aggregate royalty offsets under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.10.3(b)</u></font> reduce the royalties
                      payable to Ionis on Net Sales of a Product in the applicable country in any given period to an amount that is less than the greater of (i) [***], and (ii) [***] for such Product in such country in such period.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">22</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="zf4ccfdca4c2d413983acbaa3423f0984" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>End of Royalty Obligation</u></font>. On a country-by-country basis, other than
                      [***], 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-size: 10pt; font-family: 'Times New Roman'; 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 [***] in such country and ending when the [***] is (i) with respect to Net Sales of Products
                      in Major Markets, [***], and (ii) [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z37bbea07bab24b02a4f3b7cbc01a62a0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Royalty Examples</u></font>. <font style="font-size: 10pt; font-family: 'Times New
                        Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>9.7.2(e)</u></font> attached hereto contains examples of how royalties will be calculated under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z18929ba7821140449d9afd39f5e1bfa9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Allocation of Net Sales</u></font>. If, by reason of one or more royalty rate
                      adjustments under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2</u></font>, different royalty rates apply to Net Sales of Products from different countries, Roche will [***] such Net Sales
                      [***]. <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>9.7.2(f)</u></font> attached hereto contains
                      examples of how Net Sales of Products from different countries at different royalty rates will be [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z2799928cd9014455b7b055849be5aec7" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.8.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Apportionment of Compulsory Sublicensee Consideration</u></font>. 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 Ionis under <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 9.7</u></font> of this Agreement with respect to sales of Products by such Compulsory Sublicensee, with such adjustment calculated based on a [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z73467c6169fb437e9553dec82258fc42" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.9.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Reverse Royalty Payments to Roche for Discontinued Products</u></font>. If Ionis or
                      any of its Affiliates or Sublicensees Commercializes a Discontinued Product for which Roche has paid Ionis the license fee under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.3</u></font>, then following
                      the First Commercial Sale of such Discontinued Product by Ionis or its Affiliates or Sublicensees, Ionis will pay Roche a royalty of [***] of Annual worldwide net sales of such Discontinued Product (&#8220;<font style="font-size: 10pt;
                        font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Product Reverse Royalties</font>&#8221;). Ionis will pay Roche such Ionis Product Reverse Royalties in accordance with the provisions governing payment of
                      royalties from Roche to Ionis in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections 9.7.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>9.10</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>9.11</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>9.12</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>9.13</u></font>,
                      and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>9.14</u></font> (<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">mutatis mutandis</font>); <font style="font-size: 10pt;
                        font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Ionis&#8217; obligation to pay Roche Ionis Product Reverse Royalties will expire once Ionis has paid Roche an amount equal to [***] for such Discontinued
                      Product under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.4</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z0017a5e98d924152a00b690e7978b1ac" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.10.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Third Party Payment Obligations</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zbc2cc3be6d564dc697c408f86fba8743" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.10.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>In-License Agreements</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7476e0aa2e134bd68caf613701c4af17" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Ionis&#8217; In-License Agreements between the Effective Date and the
                          Time of Option Exercise</u></font>.&#160; Before Ionis enters into an in-license agreement with a Third Party that would impact the Developing, Manufacturing and/or Commercializing of a Product, Ionis will consult with Roche and
                      discuss the terms and conditions of such license and seek Roche&#8217;s permission to enter into such license, which will not be unreasonably denied, conditioned or delayed. Before Roche exercises the Option, Ionis will provide to Roche a
                      final list of all agreements entered into after the Effective Date by Ionis with Third Party licensors or sellers under which Ionis licensed or acquired any Licensed Intellectual Property to be licensed to Roche under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font> (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Additional Ionis In-License Agreements</font>&#8221;).&#160;









                      Any payment obligations arising under any Additional Ionis In-License Agreements as they apply to Products that:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">23</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
          </div>
          <div> <br>
          </div>
          <table cellspacing="0" cellpadding="0" id="z9b6f9330759b4fc6a89d92256f5e024b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">accrue before Option exercise will be paid by [***] as [***]; and</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z093dbd394f9a45569b581227321aad84" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">accrue after Option exercise will be paid by [***] to [***] as [***], in which case <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.10.3</u></font>
                      will apply.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z3f62eb6217d049129a4f9e31be30ea26" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Roche&#8217;s Existing In-License Agreements</u></font>. 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 [***] to such Third Parties pursuant to the applicable agreement.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z1d5d2764bb984cd6aa0128000c73e50d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.10.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>New In-Licensed Product-Specific Patents</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zf06f083c997842828cf2b4d810f7bc14" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">On a Product-by-Product basis, after Option exercise, Roche or Ionis, as the case may be, will provide the other Party written notice of any additional Third Party Patent
                      Rights promptly after it has identified such Third Party Patent Rights 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-size: 10pt; font-family: 'Times New Roman'; 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 [***] to the Third Party.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7b5b40c69d4d429ba963d00debbbdd4c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, however, Roche elects not to obtain such a license to such Additional Product-Specific Patents, Roche will so notify Ionis, and Ionis may obtain such a license to
                      such Additional Product-Specific Patents and Ionis will include such Additional Product-Specific Patents in the license granted to Roche under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that</font> Roche agrees in writing to [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z50ea3022dfe147bcb310ccf7db82f5c5" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.10.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Additional Core IP In-License Agreements</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zf7ab2dbd13d8483ca2f8747faa01bcc9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Roche will promptly provide Ionis written notice of any [***] (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Additional









                        Core IP</font>&#8221;) that Roche believes it has identified and Ionis 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) [***]. If Ionis obtains such a Third Party license, Ionis will include such Additional Core IP in the license granted to Roche under
                      <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>, and any financial obligations under such Third Party agreement will be paid solely by [***] as [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">24</font></div>
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: justify;">
        <div>
          <div> <br>
          </div>
          <table cellspacing="0" cellpadding="0" id="z2af53f47fdab41f693d9007b208e7cad" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, however, Ionis elects not to obtain such a license to such Third Party intellectual property, Ionis will so notify Roche, and Roche may obtain such a Third Party
                      license and, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2(c)(ii)</u></font>, Roche may offset an amount equal to [***] of [***] paid by Roche under such Third Party license against any
                      [***] of this Agreement in such country for [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="za60246961332415280107c64d03a3604" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Ionis does not agree with Roche that a license to such Third Party Patent Rights is necessary to [***], then Ionis 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 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 [***]. The costs of any Third Party expert engaged under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.10.3(c)</u></font> will be paid by the Party against whom the
                      Third Party lawyer makes his or her determination.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z2811d9f48fca439cad4503bef59e74e1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.11.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Payments</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z30d19b61677c428f8a13195c2b2db433" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.11.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Commencement</u></font>. 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 Ionis under this Agreement within [***] following
                      the end of each such Calendar Quarter.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zaa22271d59fa4a38b30da9aa87186646" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.11.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Royalty Reporting</u></font>. 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z2550609e0c024cdf830ba176dbc40776" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Sales in Swiss Francs on a country-by-country basis;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z856debeb571e429aa6f6f9eb5d1444e3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Net Sales in Swiss Francs on a country-by-country basis;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z88829f86be3f47f28c8178dd77960ff0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Total worldwide Net Sales in Swiss Francs;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zebdac9a9b4f14d3488d6c9d3e315ff2b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Exchange rate used for the conversion of Net Sales from Swiss Francs to U.S. Dollars pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section









                          9.11.4</u></font>;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">25</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z93f56085d8314b51ba2c2df0b7a505dc" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Royalty rate pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.1</u></font> and <font style="font-size: 10pt; font-family:
                        'Times New Roman';"><u>Section 9.7.2</u></font>, as applicable; and</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z0838a494487e4127a8bc5b74f78f3cd6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Total royalty payable in U.S. Dollars.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">In addition, Roche will include in each report under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
              9.11.2</u></font> 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z17726f22f9654ef08c515e86e8c35048" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.11.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>No Payments and Estimates</u></font>. 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 Ionis 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 Ionis a [***] 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.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z2553541748dd47e1aa58d7519653a176" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.11.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Mode of Payment</u></font>. 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 Ionis in writing, and (iii) irrevocable and non-refundable. Any
                      corrections to calculations of royalty payments previously paid will 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z090cda43208a4d8c9f31e238d5ccde99" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.11.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Records Retention</u></font>. 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 [***] after the year in which such sales occurred, and in sufficient detail to permit Ionis to confirm the
                      accuracy of the Net Sales or royalties paid by Roche hereunder.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">26</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z1421a5475dbf408b84086a91c82c5f0d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.12.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Audits</u></font>. 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 Ionis, Roche will permit an independent certified public accountant of internationally recognized standing appointed by
                      Ionis, 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 for those countries specifically requested by Ionis. 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 will share all draft
                      reports with Roche before sharing the draft audit report with Ionis and before issuing the final document. Upon completion of the audit, the accounting firm will provide both Roche and Ionis with a written report disclosing whether
                      the calculation of Net Sales and royalty payments made by Roche are correct and the specific details concerning any discrepancies (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Audit









                        Report</font>&#8221;). If any Audit Report&#160; shows 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 Ionis 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section









                          9.14</u></font>. If any Audit Report shows that Roche&#8217;s payments under this Agreement were greater than the royalty amount that should have been paid, then [***] or [***]. Ionis will pay all fees charged by such accountant
                      pursuant to the audit, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">except that</font>, if the audit determines that any additional amounts payable by Roche for an audited period exceed [***] of
                      the amount actually paid for such audited period, then, in addition to paying Ionis any unpaid amounts discovered in such audit, Roche will pay the fees and expenses charged by such accountant.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="za4deff38aabc4b7296d8d80cb5e459ee" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.13.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Taxes</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z0989edc2b2104c959721bc483557f188" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.13.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Taxes on Income</u></font>. 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z9c1001cfc0eb45b9b93739004551649d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.13.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Withholding Tax</u></font>. To the extent the paying Party is required to deduct and
                      withhold taxes on any payment, the paying Party will pay the amounts of such taxes to the proper governmental authority for the account of the receiving Party and remit the net amount to the receiving Party in a timely manner. The
                      paying Party will promptly furnish the receiving Party with proof of payment of such taxes. If documentation is necessary 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.3</u></font>, 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z034c456ed3c54d678b9e7a7b45feb0ce" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.13.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Tax Cooperation</u></font>. 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 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.13</u></font>.</font></div>
                </td>
              </tr>

          </table>
          <div> <br>
          </div>
        </div>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">27</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
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      </div>
      <div style="text-align: left;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
        </div>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.13</u></font> are to be read in
          conjunction with the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.4</u></font> below.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z8adbea014af84aaeafa5294e6251c76d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.14.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Interest</u></font>. 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 10.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">INTELLECTUAL PROPERTY</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z86580d72d94e4654b724d6b00894f90d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ownership</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z56961ec42f9745d49dc33b3b00d215d1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.1.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis Intellectual Property and Roche Intellectual Property</u></font>. As between
                      the Parties, Ionis 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zaa2225e050d84d008859c1eeacfeca9e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.1.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Agreement Intellectual Property</u></font>. 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.&#160; 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 Intellectual Property 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zbb1f4f196f8341a8b08772c7262e56e8" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.1.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Joint Patent Committee</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zc71c66f219db4b688f1c68e341c1b4f7" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Parties will establish a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Joint Patent Committee</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 10</u></font>.&#160; Ionis&#8217; obligation to
                      participate in the JPC will terminate upon the date Ionis is no longer obligated to participate in the JSC.&#160; Thereafter, Ionis will have the right, but not the obligation, to participate in JPC meetings. If Ionis chooses not to
                      participate, then Roche can dissolve the JPC. The JPC determines the invention classification for each invention arising under this Agreement. The classifications are (i) Ionis Product-Specific Patents, (ii) Ionis Collaboration
                      Patents, (iii) Roche Collaboration Patents, (iv) Jointly-Owned Collaboration Patents, (v) Ionis Core Technology Patents, and (vi) Ionis Manufacturing and Analytical Patents. The JPC will endeavor to separate the claims within such
                      Patent Rights into separate and distinct patent applications corresponding with the categories described in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.1.3(a)</u></font> to the extent possible
                      without diminishing the patentability of the inventions.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">28</font></div>
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      </div>
      <div>
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
        </div>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z4baa57ba7f314bc088b12c58085b351a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">A strategy will be discussed with regard to (x) prosecution and maintenance, defense and enforcement of (A) Ionis Product-Specific Patents, (B) Ionis Collaboration
                      Patents, (C) Roche Collaboration Patents, and (D) Jointly-Owned Collaboration Patents licensed to Roche under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font> 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.10</u></font>, Roche will have final say as to whether to obtain any licenses under Third-Party Patent Rights or Know-How.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="za5910bf23fa54a2c85279c673eed1c02" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In addition, the JPC 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 JPC (or otherwise between Ionis and Roche) over inventorship or classification, if the JPC 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.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z61bd699d5a954d6e8185b207dbdb9975" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The JPC will comprise an equal number of members from each Party. The JPC 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 10</u></font>. The JPC will determine by unanimous consent the JPC operating procedures at its first meeting. To the
                      extent reasonably requested by either Party, the JPC 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 JPC 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.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">29</font></div>
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z7ab5a0ccffa44024ad85f68326d98674" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Prosecution and Maintenance of Patents</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z8285929522b64029a8c968844b6e94ab" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patent Filings</u></font>. The Party responsible for Prosecution and Maintenance of
                      any Patent Rights as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.2</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.3</u></font> 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z65869447a79a46d7acaa95a00f0ddabb" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Licensed Patents and Roche Patents</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z58d3a7e1e0a849e7bf337f3067250a0d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Licensed Patents</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z6c03141289024ab6b183eeb94ddb0c44" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis Core and Manufacturing Patents</u></font>. Ionis will at all times control and
                      be responsible for all aspects of (i) the Ionis Core Technology Patents, and (ii) the Ionis Manufacturing and Analytical Patents.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zd55ee16eda9c4f27adf113621d996013" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis Product-Specific Patents</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 144pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(1)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Before Option Exercise</u></font>. Before Option exercise, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.3</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4</u></font>, at Ionis&#8217; expense, Ionis will control and be responsible for Prosecuting and Maintaining the Ionis Product-Specific Patents.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 144pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(2)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; <font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>After Option Exercise</u></font>. After Option exercise, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.3</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4</u></font>, at Roche&#8217;s expense, so long as the applicable license to Roche under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>
          is in effect, Roche will control and be responsible for all aspects of the Prosecution and Maintenance of all Ionis Product-Specific Patents (including any Jointly-Owned Collaboration Patents that are also Product-Specific Patents) Covering
          Products 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 Ionis, in which case following any such
          assignment all licenses granted in this Agreement by Ionis to Roche under such Patent Rights will become non-exclusive and the exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>will no longer apply to such Patent Rights.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zff969b73876a406fa7b592a88eb1715b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Roche Patents and Roche Collaboration Patents</u></font>. Roche will control and be
                      responsible for all aspects of the Prosecution and Maintenance of all Roche Patents and Roche Collaboration Patents, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.3</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">30</font></div>
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="zf01dc1e7366344cf8f6e5d605d6b4bb1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Jointly-Owned Collaboration Patents</u></font>. The Parties will decide through the
                      JPC the appropriate Party to control and be responsible for Prosecuting and Maintaining all Jointly-Owned Collaboration Patents not provided for above.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z1e5a890873544816921a673893c8bfb5" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Other Matters Pertaining to Prosecution and Maintenance of Patents</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z5831968e99b0420bb3efdbab819404d4" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Each Party will keep the other Party informed through the JPC 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.2</u></font> or this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4</u></font>, 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.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z9f8bff0e55f343c5b25dda7d3f24a006" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Roche elects (i) not to file and prosecute patent applications for the Jointly-Owned Collaboration Patents or Ionis Product-Specific Patents that have been licensed to
                      Roche under this Agreement for which Roche has responsibility for Prosecution and Maintenance pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.2</u></font> or <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 10.2.3</u></font> (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche-Prosecuted Patents</font>&#8221;) in a particular country, (ii)
                      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 (iii) not to file and prosecute patent applications for the Roche-Prosecuted Patent in a particular country following a written request from Ionis to file and prosecute in such country, then Roche will so notify Ionis
                      promptly in writing of its intention in good time to enable Ionis to meet any deadlines by which an action must be taken to establish or preserve any such Patent Right in such country; and Ionis 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 Ionis to file
                      for, or continue to Prosecute and Maintain or enforce, or otherwise pursue such Roche-Prosecuted Patent in such country. Notwithstanding anything to the contrary in this Agreement, if Ionis assumes responsibility for the Prosecution
                      and Maintenance of any such Roche-Prosecuted Patent under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4(b)</u></font>, Ionis will have no obligation to notify Roche if Ionis intends to abandon
                      such Roche-Prosecuted Patent. The analogous situation will apply <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">mutatis mutandis</font> with regard to Patent Rights (excluding Ionis Core Technology
                      Patents and Ionis Manufacturing and Analytical Patents) for which Ionis has responsibility for Prosecution and Maintenance pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.2</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.3</u></font>.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">31</font></div>
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        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z2fce71912ffa4179a3a63331766084fc" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Parties, through the JPC, 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.</font></div>
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          </table>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zb0c650ffdbad4accad0fb19e6806e5df" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If the Party responsible for Prosecution and Maintenance pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.3</u></font> 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 <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 10.3.1</u></font>) 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4(d)</u></font>, such Party will have no obligation to notify the other Party of any intention of such
                      Party to abandon such Jointly-Owned Collaboration Patents.</font></div>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7a2a561f44fc4928899539c55c625ce7" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In addition, the Parties will consult, through the JPC, 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.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z14909ff279134253bd408f83811eca64" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patent Costs</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z0198e658dd8e45ab9477c9912b459f15" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.3.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Jointly-Owned Collaboration Patents</u></font>. Unless the Parties agree otherwise,
                      Ionis and Roche will share equally the Patent Costs associated with the Prosecution and Maintenance of Jointly-Owned Collaboration Patents; <font style="font-size: 10pt; font-family: 'Times New Roman'; 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, title and interest in and to such Jointly-Owned Collaboration Patents.</font></div>
                </td>
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          </table>
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      </div>
      <div><br>
      </div>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">32</font></div>
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          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z50f1bed11efd44da9c3f5ed56099128b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.3.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Licensed Patents and Roche Patents</u></font>. Except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.3.1</u></font>, 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 <font style="font-size: 10pt; font-family: 'Times New
                        Roman';"><u>Section 10.2</u></font>; <font style="font-size: 10pt; font-family: 'Times New Roman'; 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 Ionis Product-Specific Patents; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that</font>, Roche may decline to pay for filing, prosecuting and
                      maintaining any such Ionis Product-Specific Patents in a particular country or particular countries, in which case all licenses granted in this Agreement by Ionis to Roche under such Patent Rights will become non-exclusive and the
                      exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font> will no longer apply to such Patent Rights.</font></div>
                </td>
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        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zd06ba6f2f9914c94ba843a2b2771d5e9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Defense of Claims Brought by Third </u></font><font style="font-size: 10pt;
                        font-family: 'Times New Roman'; font-weight: bold;"><u>Parties</u></font>.</font></div>
                </td>
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      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zf9fb225756dd43ad867d74460f880d19" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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) Ionis 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)&#160; 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.&#160; If the Party having the first right to defend against such Proceeding (the &#8220;<font style="font-size: 10pt; font-family:
                        'Times New Roman'; 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 <font style="font-size:
                        10pt; font-family: 'Times New Roman';"><u>Section 10.4</u></font>, 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-size: 10pt; font-family:
                        'Times New Roman'; 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. Each Party may at its own expense and with its own counsel join any defense initiated or directed by the other Party under this <font style="font-size: 10pt; font-family: 'Times New
                        Roman';"><u>Section 10.4</u></font>. Each Party will provide the other Party with prompt written notice of the commencement of any such Proceeding under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                          10.4</u></font>, 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.</font></div>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">33</font></div>
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            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential<br>
              <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="zd02bedc8734e4b4488b15274b907e951" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Discontinued Product</u></font>. 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, Ionis 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 Ionis in defending such Proceeding and cooperate in any such litigation at the request and expense of Ionis. Each Party may at its own
                      expense and with its own counsel join any defense directed by the other Party. Ionis will provide Roche with prompt written notice of the commencement of any such Proceeding, or of any allegation of infringement of which Ionis becomes
                      aware and that is of the type described in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.2</u></font>, and Ionis will promptly furnish Roche with a copy of each communication relating to the
                      alleged infringement received by Ionis.</font></div>
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      </div>
      <div><br>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z32daf970b1b149e990ebbd0ba30da4ed" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Interplay Between Enforcement of IP and Defense of Third Party Claims</u></font>.&#160;&#160;
                      Notwithstanding the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.1</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.2</u></font>, to the
                      extent that a Party&#8217;s defense against a Third Party claim of infringement under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4</u></font> 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section









                          10.5</u></font> will apply to the enforcement of such other Party&#8217;s Know-How or Patent Rights or the defense of such invalidity claim (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font>, 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                          10.5</u></font>, 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section









                          10.5</u></font>, to enforce such Know-How or Patent Rights or defend such invalidity claim).</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zff8cec076e8840fe838c6907b053ea37" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Enforcement of Patents Against Competitive Infringement</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z5a80be6eab194c7c8b9ae32b80f8efc9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.5.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Duty to Notify of Competitive Infringement</u></font>. 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 Factor B in the Field (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competitive</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided,
                        however</font>, that for cases of Competitive Infringement under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.5.7</u></font> below, such written notice will be given within ten (10) Business Days.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z9d01435e6f7d40698e18a09148a24d9d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.5.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Before Option Exercise</u></font>. For any Competitive Infringement occurring after
                      the Effective Date but before Option exercise, Ionis 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">however</font>, Ionis will have the sole right to control such
                      litigation.&#160; Ionis will provide Roche with prompt written notice of the commencement of any such Proceeding, and Ionis will keep Roche apprised of the progress of such Proceeding.&#160; If Ionis 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 if Ionis 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that </font>Ionis will have the right to be represented in any such action by counsel of its own choice at its
                      own expense.&#160; Notwithstanding the foregoing, Ionis will at all times have the sole right to institute, prosecute, and control any Proceeding under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.5.2</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#160;</font>to the extent involving any Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">34</font></div>
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="zdf9f9a3410644ad4afe75ae7a551cc2b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.5.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>After Option Exercise</u></font>.&#160; 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 Ionis will have the right, at its own expense, to be represented in that
                      action by counsel of its own choice, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">however</font>, Roche will have the right to control such litigation.&#160; 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 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), Ionis 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.&#160; Notwithstanding the foregoing, Ionis will at all times have the sole right to institute, prosecute, and control any Proceeding
                      under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.5.3</u></font> to the extent involving any Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z2f09ffb84565449eb5254a8cd8f009d1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.5.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Joinder</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z3f6dbf8a21d44a4e967fb2d56ced6f55" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If a Party initiates a Proceeding in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.5</u></font>, 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section









                          10.5.5</u></font>, the costs and expenses of each Party incurred pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.5.4(a)</u></font> will be borne by the Party initiating such
                      Proceeding.</font></div>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="ze2b408fa01e041f490b63451a8f2d652" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If one Party initiates a Proceeding in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.5</u></font>, 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.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">35</font></div>
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z30adbefb265144dcb15d5c3e825ca1c6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.5.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Share of Recoveries</u></font>. Any damages or other monetary awards recovered with
                      respect to a Proceeding brought pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.5</u></font> will be shared as follows:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zc4a99b0c4ead4f89bb39a5b02ce17555" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">pro rata</font> if insufficient to cover the totality of such expenses); then</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z3f11b28c29bb45fcaaa13a0393b2045c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any remaining proceeds constituting direct or actual damages for acts of infringement occurring before Roche&#8217;s exercise of the Option will be (i) [***]; or (ii) [***];
                      then</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="za69642650319410f85766948b219a1cc" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any remaining proceeds constituting direct or actual damages for acts of infringement occurring after Roche&#8217;s exercise of the Option will be treated [***], and [***];
                      then</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zb15e6f9365b7417e83384959c113ab33" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 [***] of such proceeds and the other Party will receive and retain [***] of such proceeds.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z3683d51b8a6f439bbe1aa54e05b6dfad" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.5.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Settlement</u></font>. Notwithstanding anything to the contrary under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 10</u></font>, neither Party may enter a settlement, consent judgment or other voluntary final disposition of a suit under this <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>ARTICLE 10</u></font> 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zc97e8d8bc035418ea33d0b7467b3c918" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.5.7.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>35 U.S.C. &#167; 271(e)(2) Infringement</u></font>. Notwithstanding anything to the
                      contrary in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.5</u></font>, solely with respect to Licensed Patents, for a Competitive Infringement under 35 U.S.C. &#167; 271(e)(2), the time period set
                      forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.5.2</u></font> 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z0f80e608934245999b964f7118e749a2" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Other Infringement</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z92232222fe9643d6bd22dc9575a19026" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.6.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Jointly-Owned Collaboration Patents</u></font>. 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.6.1</u></font> 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-size: 10pt; font-family: 'Times New Roman';
                        font-style: italic;">pro rata</font> if insufficient to cover the totality of such expenses); (ii) any remaining proceeds constituting direct damages will be [***] and will retain the remainder of such proceeds, 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                          10.6.1</u></font>, [***] of such proceeds; and (B) if only one Party initiates the Proceeding pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.6.1</u></font>, such Party will receive
                      [***] of such proceeds and the other Party will receive [***] of such proceeds.</font></div>
                </td>
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          </table>
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      </div>
      <div><br>
      </div>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">36</font></div>
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z60d45343fae74359a4d6cd81cbca2943" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.6.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patents Solely Owned by Ionis</u></font>. Ionis will retain all rights to pursue an
                      infringement of any Patent Right solely owned by Ionis which is other than a Competitive Infringement and Ionis will retain all recoveries with respect thereto.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z684d8cd496894a028ddda9f051c4150e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.6.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patents Solely Owned by Roche</u></font>. 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="ze7167d9eab0f48a6bc16060041be7cfe" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.7.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patent Listing</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z5d271bcbc85b491199c96ab6b2e2c110" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.7.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Roche&#8217;s Obligations</u></font>. Roche will promptly, accurately and completely list,
                      with the applicable Regulatory Authorities during the Agreement Term, all applicable Patent Rights that Cover a Product. Prior to such listings, the Parties will meet, through the JPC, 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 JPC 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 Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents, regardless of which Party owns such
                      Patent Rights.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zb2ffc89e01ca47ad809f6cfd25ba4ea2" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.7.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Obligations</u></font>. Ionis 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 JPC, to evaluate and identify all
                      applicable Patent Rights, and Ionis will have the right to review, where reasonable, original records relating to any invention for which Patent Rights are being considered by the JPC for any such listing. Notwithstanding the
                      preceding sentence, Ionis 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zae5c39f1115f4386adfdad42646d6c66" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.8.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Joint Research Agreement under the Leahy-Smith America Invents Act</u></font>. If a
                      Party intends to invoke its rights under 35 U.S.C. &#167; 102(c) of the Leahy-Smith America Invents Act, it will notify the other Party and neither Party will make an election under such provision when exercising its rights under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 10</u></font> without the prior written consent of the other Party (such consent not to be unreasonably withheld, conditioned or delayed), and the Parties will use
                      reasonable efforts to cooperate and coordinate their activities with such Party with respect to any submissions, filings or other activities in support thereof. The Parties acknowledge and agree that this Agreement is a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">joint research agreement</font>&#8221; as defined in 35 U.S.C. &#167; 100(h).</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">37</font></div>
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      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="zbf90587c8cc743be85c9860a5c88aa4c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.9.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Obligations to Third Parties</u></font>. Notwithstanding any of the foregoing, each
                      Party&#8217;s rights and obligations with respect to Licensed Intellectual Property under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 10</u></font> will be subject to the Third Party rights and
                      obligations under any (i) Third Party agreements for Additional Product-Specific Patents, the restrictions and obligations of which Roche has agreed to under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                          9.10.2(b)</u></font>, (ii) the Prior Agreement, and (iii) Additional Ionis In-License Agreements; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that, to the extent
                      that Ionis 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, Ionis will act in such regard with respect to such
                      Patent Rights at Roche&#8217;s direction.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z01d7c3988a6a4781bbf3ac43e2fc3117" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.10.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Additional Right and Exceptions</u></font>. Notwithstanding any provision of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 10</u></font>, but subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.3</u></font>,&#160; Ionis retains the sole right to
                      Prosecute and Maintain Ionis Core Technology Patents and Ionis Manufacturing and Analytical Patents during the Agreement Term and to control any enforcement of Ionis Core Technology Patents and Ionis 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 Ionis and Covering the Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents
                      is at risk. If Ionis determines, in Ionis&#8217; sole discretion, not to enforce any Ionis Core Technology Patents or Ionis 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 Ionis&#8217; failure to enforce such Patent Rights has on Products.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zd42be678dd7149808c3e6e3e54c1a28e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.11.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patent Term Extension</u></font>.<font style="font-size: 10pt; font-family: 'Times
                        New Roman'; 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 Ionis Product-Specific Patents and Jointly Owned Collaboration Patents that are also Product-Specific Patents will be extended and what extensions will be sought.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z3dfa86250cc447829a8c93630d20247e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.12.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>No Challenge</u></font>. If, during the Agreement Term, solely with respect to rights
                      to the Ionis Product-Specific Patents that are included (or, prior to Option exercise, are eligible to be included) in a license granted to Roche under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>,
                      Roche, its Affiliates or Sublicensees, in any 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 Ionis
                      Product-Specific 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 Ionis Product-Specific Patents, then
                      unless, within thirty (30) days after written notice from Ionis, Roche rescinds any actions brought by Roche, its Affiliates, or Sublicensees, Ionis may, to the extent permitted under Applicable Law, terminate this Agreement and the
                      provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.1</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.2</u></font> will apply; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">[***]</font>.</font></div>
                </td>
              </tr>

          </table>
          <div> <br>
          </div>
        </div>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">38</font></div>
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      </div>
      <div style="text-align: left;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
        </font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 11.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">REPRESENTATIONS AND WARRANTIES</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zef2df7ee31f24dccad48b687c96e753d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Representations and Warranties of Both Parties</u></font>. Each Party hereby
                      represents and warrants to the other Party, as of the Effective Date, that:</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z0ddfca794cb84d1a9899000842d1126c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.1.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z68f402d284884f5b8a41c9b7a4342e6d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.1.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zfa3b60edfa084713b881544e2f4918a3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.1.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zbb92505a47294bd6bc60342c496a328d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.1.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z3e13de3bd952455f8c55cf193e40dca1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.1.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">to the best of its knowledge and belief, other than with respect to the HSR Act, 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</font></div>
                </td>
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        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z29b6d8ff093747f3ba242d8a9be1aec2" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.1.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that </font>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 Non-Clinical Studies or Clinical Studies of a Product and its activities under the Development Plan.</font></div>
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      <div><br>
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      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">39</font></div>
        <div id="DSPFPageBreak" style="page-break-after:always;">
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z30262ed9cb9c46e599289fc6b228dda5" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Representations and Warranties of Ionis</u></font>. Ionis hereby represents and
                      warrants to Roche, as of the Effective Date, that:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z297bb08a0da3459490a8d6c133c1e9ec" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.2.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">To the best of its knowledge and belief, there are no additional licenses under any intellectual property owned or Controlled by Ionis or its Affiliates as of the
                      Effective Date that would be required in order for Roche to further Develop and Commercialize a Product existing on the Effective Date.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z5766ee97db3c4d708b834f4031db79dd" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.2.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Licensed Intellectual Property existing as of the Effective Date constitutes all of the Patent Rights and Know-How Controlled by Ionis as of the Effective Date that
                      are necessary to Develop, Manufacture or Commercialize Products existing on the Effective Date in the Field. Ionis has not previously assigned, transferred, conveyed or otherwise encumbered its right, title and interest in the
                      Licensed Intellectual Property in a manner that conflicts with any rights granted to Roche hereunder.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zabd68e5f2997417eb980c596557651c7" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.2.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">There are no claims, judgments or settlements against or owed by Ionis or its Affiliates or pending against Ionis or, to the best of Ionis&#8217; knowledge, threatened against
                      Ionis, in each case relating to the Licensed Intellectual Property that could impact activities under this Agreement. To the best of Ionis&#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 Licensed Intellectual Property that would impact activities
                      under this Agreement.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z182f917d4c9a47e0bbe0825647d29242" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.2.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New
                        Roman';"><u> 11.2.4(a)</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 11.2.4(b)</u></font>
                      and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 11.2.4(c)</u></font> set forth true, correct and
                      complete lists of all Ionis Core Technology Patents, Ionis Manufacturing and Analytical Patents, and Ionis Product-Specific Patents that apply to Products as of the Effective Date, and indicates whether each such Patent Right is owned
                      by Ionis or licensed by Ionis from a Third Party and if so, identifies the licensor or sublicensor from which the Patent Right is licensed.&#160; Ionis 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zb39235f47e46497e8f2faf940aee7165" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.2.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">(a) There is no fact or circumstance known by Ionis that would cause Ionis to reasonably conclude that any Licensed Patent is invalid or un-enforceable, (b) there is no
                      fact or circumstance known by Ionis that would cause Ionis 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 Ionis Product-Specific Patents that would be licensed by Ionis to Roche upon Option exercise under this
                      Agreement is currently involved in any interference, reissue, re-examination, cancellation or opposition proceeding and neither Ionis, 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 Ionis&#8217; knowledge and belief, Roche&#8217;s practice of the inventions claimed in the Ionis Product-Specific Patents in the performance of the Development Plan contemplated as of
                      the Effective Date will not [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">40</font></div>
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        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="ze28bf4dcb5b646ae98ae7c92a889b3c9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.2.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New
                        Roman';"><u> 11.2.6</u></font> is a complete and accurate list of the one Prior Agreement, which is the only agreement that creates Third Party Obligations that affect the rights granted by Ionis to Roche under this Agreement.&#160;
                      Ionis is not in default of such Prior Agreement, and the applicable Third Party, to the best knowledge of Ionis, has no grounds upon which to claim that Ionis is in default that would affect the rights granted by Ionis to Roche under
                      this Agreement. To the best knowledge of Ionis, the applicable Third Party is not in default with respect to a material obligation under such Prior Agreement that would adversely impact activities under this Agreement.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zf417b439bf5d4d9c90ae0e0f6fd223e3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.2.7.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zd28ff2fc12774475ac344b0a1c95ca59" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis Covenants</u></font>. Ionis hereby covenants to Roche that, except as expressly
                      permitted under this Agreement:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zaaaf9a7f694d4a648c06f451b33c2b82" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.3.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will promptly amend <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u> 11.2.4(a)</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New
                        Roman';"><u> 11.2.4(b)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 11.2.4(c)</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"> and submit such amended </font>Schedules to Roche if Ionis <font style="font-size: 10pt; font-family: 'Times New Roman';">becomes aware that any </font>Ionis Core
                      Technology Patents<font style="font-size: 10pt; font-family: 'Times New Roman';">, </font>Ionis Manufacturing <font style="font-size: 10pt; font-family: 'Times New Roman';">and Analytical Patents or </font>Ionis Product-Specific
                      Patents <font style="font-size: 10pt; font-family: 'Times New Roman';">are not properly identified on such Schedule.</font></font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z48e33efbfb4e43edacef9eb3da498d30" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.3.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">during the Agreement Term, Ionis will maintain and not breach (i) the Prior Agreement, (ii) any Additional Ionis In-License Agreements (if any), and (iii) any agreements
                      with Third Parties entered into after the Option exercise (including Third Party agreements for Additional Product-Specific Patents described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.10.2(b)</u></font>
                      that provide a grant of rights from such Third Party to Ionis that are Controlled by Ionis and are licensed or may become subject to a license from Ionis to Roche for a Product under this Agreement (collectively (i), (ii), and (iii),
                      &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">New Third Party Licenses</font>&#8221;);</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z66d4343be72e4fe5a2503df2386e5363" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.3.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will promptly notify Roche of any material breach by Ionis or a Third Party of any New Third Party License, and in the event of a breach by Ionis, will permit Roche
                      to cure such breach on Ionis&#8217; behalf upon Roche&#8217;s request;</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z9f03aa8ba76c46fea385dbf617cf26cd" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.3.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will not amend, modify or terminate any 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;</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">41</font></div>
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="ze3dfe848c7bf4821906991f2caa658cc" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.3.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis 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;</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z24cd4d83ac0640aeafe81facf736014d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.3.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will cause its Affiliates, licensees and sublicensees to comply with the terms of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font>;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zec08dd280a2a4e1ca150d6e6736351a8" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.3.7.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">all employees and contractors of Ionis performing Development activities hereunder on behalf of Ionis will be obligated to assign all right, title and interest in and to
                      any inventions (or grant a license to Ionis or an option to obtain such a license) developed by them, whether or not patentable, to Ionis or such Affiliate, respectively, as the sole owner thereof; and</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zd2adeecb8cde4380bd2c8a1030dd96a1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.3.8.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">if, after the Effective Date, Ionis 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, Ionis will make such technology available to Roche on
                      commercially reasonable terms.</font></div>
                </td>
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          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z5c3d82a14c1a4d70bf6cf349304cef94" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>DISCLAIMER</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';
                        font-weight: bold;">.</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 IONIS 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>
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          </table>
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      </div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 12.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">INDEMNIFICATION; INSURANCE</font></div>
      <div><br>
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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Indemnification by Roche</u></font>. Roche will indemnify, defend and hold harmless
                      Ionis 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-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Claims</font>&#8221;) based upon:</font></div>
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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.1.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the gross negligence or willful misconduct of Roche, its Affiliates <font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.1.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any breach of any representation or warranty or express covenant made by Roche under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 11</u></font>
                      or any other provision under this Agreement;</font></div>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">42</font></div>
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            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
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          <table cellspacing="0" cellpadding="0" id="z4c86f173167c4d58b8c828fb32046042" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.1.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the Development or Manufacturing activities that are conducted by <font style="font-size: 10pt; font-family: 'Times New Roman';">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="font-size: 10pt; font-family: 'Times New Roman';">or</font> on behalf of Ionis pursuant to this Agreement);
                      or</font></div>
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      <div style="text-align: justify;">
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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.1.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the Commercialization of a Product by or on behalf of Roche or its Affiliates or Sublicensees;</font></div>
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      <div><br>
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      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>except</u></font>, in each case above, to the
          extent such Claim arose out of or resulted from or is attributable to any acts or omissions of Ionis <font style="font-size: 10pt; font-family: 'Times New Roman';">or</font> its Affiliates, licensees, Sublicensees or contractors, and its or
          their respective directors, officers, employees and agents or other circumstance for which Ionis has an indemnity obligation pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.2</u></font>.</font></div>
      <div><br>
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      <div style="text-align: justify;">
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          <table cellspacing="0" cellpadding="0" id="zc20de777e3e34c2fabd4063e0daf55fe" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Indemnification by Ionis</u></font>. Ionis 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>
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      <div><br>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z0893a4216cdf45e188e5e39c16f31dcc" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.2.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the gross negligence or willful misconduct of Ionis, its Affiliates <font style="font-size: 10pt; font-family: 'Times New Roman';">or</font> Sublicensees <font style="font-size: 10pt; font-family: 'Times New Roman';">or</font> its or their respective directors, officers, employees and agents, in connection with Ionis&#8217; performance of its obligations or exercise of its rights under this
                      Agreement;</font></div>
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        <div>
          <table cellspacing="0" cellpadding="0" id="z602128cab6b44b73988f5616b07a8e7c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.2.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any breach of any representation or warranty or express covenant made by Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 11</u></font>
                      or any other provision under this Agreement;</font></div>
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      <div><br>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z7aa3a5b7259f48e68e4150209c3f6157" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.2.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any Development or Manufacturing activities that are conducted by <font style="font-size: 10pt; font-family: 'Times New Roman';">or</font> on behalf of Ionis or its
                      Affiliates or Sublicensees (which will exclude any Development or Manufacturing activities that are conducted by <font style="font-size: 10pt; font-family: 'Times New Roman';">or</font> on behalf of Roche pursuant to this Agreement);
                      or</font></div>
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      <div><br>
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      <div style="text-align: justify;">
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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.2.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any development, manufacturing or commercialization activities that are conducted by <font style="font-size: 10pt; font-family: 'Times New Roman';">or</font> on behalf
                      of Ionis or its Affiliates or Sublicensees with respect to a Product or a Discontinued Product;</font></div>
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      <div><br>
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      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>except</u></font>, 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="font-size: 10pt; font-family: 'Times New Roman';">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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font>.</font></div>
      <div><br>
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      <div style="text-align: justify;">
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          <table cellspacing="0" cellpadding="0" id="z8dcbb0f9e4c04cc2aee059e60aa6d305" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Procedure</u></font>. If a Person entitled to indemnification under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.2</u></font> (an &#8220;<font style="font-size: 10pt; font-family: 'Times
                        New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4</u></font> 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font> or <font style="font-size:
                        10pt; font-family: 'Times New Roman';"><u>Section 12.2</u></font>, as the case may be, for Claims settled or compromised by the Indemnitee without the indemnifying Party&#8217;s prior written consent.</font></div>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">43</font></div>
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            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" id="z8f2b54f5103e435796802e3497665f1d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Insurance</u></font>.</font></div>
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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.4.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Insurance Obligations</u></font>. Ionis will maintain, at its cost, reasonable
                      insurance against liability and other risks associated with its activities contemplated by this Agreement (including product liability for a Discontinued Product), 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. Ionis will maintain such insurance throughout the Agreement Term and for five (5) years thereafter, and Ionis will furnish to Roche evidence of any insurance required under
                      this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.4.1</u></font>, upon request.</font></div>
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      <div><br>
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      <div style="text-align: justify;">
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          <table cellspacing="0" cellpadding="0" id="z96a8066c69594b639bdee02cbef004e6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.4.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Roche&#8217;s Insurance Obligations</u></font>. Roche hereby represents and warrants to
                      Ionis 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 Ionis evidence of such insurance, upon request.</font></div>
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      <div><br>
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        <div>
          <table cellspacing="0" cellpadding="0" id="zea02eea475504f3c955c20cc545fc8a9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>LIMITATION OF CONSEQUENTIAL DAMAGES</u></font>. <font style="font-size: 10pt;
                        font-family: 'Times New Roman'; font-weight: bold;">EXCEPT FOR (a) CLAIMS OF A THIRD PARTY THAT ARE SUBJECT TO INDEMNIFICATION UNDER THIS </font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>ARTICLE









                          12</u></font>,<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> (b) CLAIMS ARISING OUT OF A PARTY&#8217;S WILLFUL MISCONDUCT OF THIS AGREEMENT, (c) A PARTY&#8217;S BREACH OF </font><font style="font-size:
                        10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>ARTICLE 5</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">, (d) A BREACH OF </font><font style="font-size: 10pt; font-family:
                        'Times New Roman'; font-weight: bold;"><u>SECTION 13.4.1(b)</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> BY ROCHE OR ITS AFFILIATES OR (e) 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>
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        <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">44</font></div>
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        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
        </div>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 13.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">TERM; TERMINATION</font></div>
      <div><br>
      </div>
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          <table cellspacing="0" cellpadding="0" id="z01c016c975bd469abbaf14f08d087a35" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Agreement Term; Expiration</u></font>. This Agreement is effective as of the
                      Effective Date and, unless earlier terminated pursuant to the other provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 13</u></font>, will continue in full force and effect until this
                      Agreement expires as follows:</font></div>
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        <div>
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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.1.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">on a country-by-country and Product-by-Product basis, on the date of expiration of all payment obligations by the Commercializing Party under this Agreement with respect
                      to such Product (or such Discontinued Product) in such country; and</font></div>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z784bf0f5f9824b0a812e2e17c86126eb" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.1.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.1.1</u></font>; and</font></div>
                </td>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="zf792d981a866439db06fc1bb739d947c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.1.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">where Roche has not provided Ionis a written notice stating Roche is exercising its Option under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section









                          6.1</u></font> by the Option Deadline.</font></div>
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      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The period from the Effective Date until the date of expiration of this Agreement pursuant to this <font style="font-size: 10pt;
            font-family: 'Times New Roman';"><u>Section 13.1</u></font> is the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font>, is not terminated early) under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.1.1</u></font>
          or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.1.2</u></font> in a particular country, then, effective upon such expiration, Ionis will and hereby does grant to Roche a fully paid-up and irrevocable
          non-exclusive, sublicensable license under the Licensed Intellectual Property to Manufacture, Develop and Commercialize the Product that is the subject of such expiration in such country.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z1c13545556284c83afcfeda4692bce6b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination of the Agreement</u></font>.</font></div>
                </td>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" id="z01ac2e73792447feabe41c69b3cca052" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.2.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Roche&#8217;s Termination for Convenience</u></font>.<font style="font-size: 10pt;
                        font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>After payment by Roche of the option&#160; fee under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.1</u></font>, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.1</u></font> below, Roche may terminate this Agreement in its entirety or in part on a country-by-country or Product-by-Product basis for convenience by
                      providing (i) ninety (90) days&#8217; written notice to Ionis of such termination if the Product has not been sold commercially, or (ii) one hundred eighty (180) days&#8217; written notice to Ionis of such termination if the Product has been sold
                      commercially. </font></div>
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      <div><br>
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        <div>
          <table cellspacing="0" cellpadding="0" id="z33f77fd3f2bf4437b0c1c865bd368fb4" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.2.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination for Material Breach</u></font>.</font></div>
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      <div><br>
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      <div style="text-align: justify;">
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          <table cellspacing="0" cellpadding="0" id="z057b80012f6048639921a82bc3271f90" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Roche&#8217;s Right to Terminate</u></font>. If Roche believes that Ionis is in material
                      breach of this Agreement (other than with respect to a failure to use Commercially Reasonable Efforts under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1</u></font>, which is governed by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.3</u></font> below), then Roche may deliver notice of such material breach to Ionis. If the breach is curable, Ionis will have sixty (60) days to cure such
                      breach. If Ionis 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 Ionis.</font></div>
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            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z950c3cc479fd494aa0a6d7c335c08215">

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                <td style="width: 36pt; vertical-align: top; align: right; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">(b)</td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Right to Terminate</u></font>. If Ionis believes that Roche is in material
                      breach of this Agreement (other than with respect to a failure to use Commercially Reasonable Efforts under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1</u></font> or <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 8.1</u></font>, which is governed by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.3</u></font> below), then Ionis 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, Ionis may terminate this Agreement by providing written notice to
                      Roche.</font></div>
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      <div><br>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0dc69defb0bc4ab7b317042762724ed7">

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                <td style="width: 36pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.2.3.</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Remedies for Failure to Use Commercially Reasonable Efforts</u></font>.</font></div>
                </td>
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        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z386f96c307fa4627b650daf97b00756d">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Ionis, in Roche&#8217;s reasonable determination, fails to use Commercially Reasonable Efforts to conduct the activities Ionis agreed to perform under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1</u></font> prior to Option exercise, Roche will notify Ionis and, within thirty (30) days thereafter, Ionis 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 Ionis&#8217; use of Commercially Reasonable Efforts for such activities in <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 3.1</u></font>. Following such a meeting, if Ionis fails to use Commercially Reasonable Efforts as contemplated by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section










                          3.1</u></font>, then subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.4</u></font> 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.3</u></font> below, which such election is Roche&#8217;s sole and exclusive
                      remedy if Ionis fails to use Commercially Reasonable Efforts in the activities contemplated in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1</u></font> prior to Option exercise.<br>
                    </font></div>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf0537c3cf3f14c33b2659596e818f191">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Roche, in Ionis&#8217; reasonable determination, fails to use Commercially Reasonable Efforts under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section










                          3.1</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.1</u></font> above, Ionis will notify Roche and, within thirty (30) days thereafter, Ionis 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 under <font style="font-size: 10pt; font-family: 'Times
                        New Roman';"><u>Section 3.1</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.1</u></font>. Following such a meeting, if Roche fails to use Commercially Reasonable Efforts as contemplated by
                      <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1</u></font>&#160; or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.1</u></font>, then subject to <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 13.2.4</u></font> below, Ionis will have the right, at its sole discretion, to terminate this&#160; Agreement.</font></div>
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      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze3ce16fbc4454374b4e4c44170247146">

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                <td style="width: 36pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.2.4.</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Disputes Regarding Material Breach</u></font>. Notwithstanding the foregoing, if the
                      Breaching Party in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.2</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.3</u></font> 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.2</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.3</u></font>,
                      or trigger the alternative remedy provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.3</u></font>, as applicable, unless and until it has been determined in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.1</u></font> 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. 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>
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            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb52a2d7bd3d64b54aab6c54c952af614">

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                <td style="width: 36pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.2.5.</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination for Insolvency</u></font>.</font></div>
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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 is served with an involuntary petition against it, filed in any insolvency proceeding, and such petition is not dismissed within ninety (90) days after
                      the filing thereof; or if the other Party is a party to any dissolution or liquidation; or if the other Party makes an assignment of substantially all of its assets for the benefit of creditors.</font></div>
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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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-size: 10pt; font-family: 'Times New Roman'; 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. 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.</font></div>
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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.3.</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Alternative Remedy to Termination Available to Roche Prior to Option Exercise</u></font>.
                      If Roche elects, pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.3(a)(ii)</u></font>,&#160; to exercise the alternative remedy provisions of this <font style="font-size: 10pt; font-family:
                        'Times New Roman';"><u>Section 13.3</u></font> in lieu of terminating this Agreement by providing written notice of such election to Ionis in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                          13.2.3(a)</u></font>, then this Agreement will continue in full force and effect with the following modifications:</font></div>
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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will have no further obligations under the Development Plan, and Roche is responsible for the continued Development and Commercialization of IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> (including meeting all remaining performance obligations under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.1</u></font>);</font></div>
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        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">47</font></div>
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            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z542dcbb3550848bf8a2430d0917ebf6b">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">effective as of the date of Roche&#8217;s notice to Ionis electing the alternative remedy provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section










                          13.3</u></font>, Roche will be deemed for all purposes of this Agreement to have exercised the Option;</font></div>
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      <div style="text-align: justify;">
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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Roche will have and Ionis grants, the exclusive license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font>;</font></div>
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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will perform its obligations under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2</u></font>, assign and transfer the IND for
                      IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to Roche, and transfer, at Roche&#8217;s request, any Phase 2 Trials then-being administered by Ionis, all within ninety (90) days after Roche
                      electing to exercise its alternative remedies under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.3</u></font>; and</font></div>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z99c01f41f2e348b5bab6fbeaddc88f30">

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                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the financial provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 9</u></font> will be modified as follows:</font></div>
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      <div style="text-align: justify;">
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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Roche will [***]; and</font></div>
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        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zcb8490526d854ab0beb0f6e74de73079">

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                <td style="width: 108pt;"><br>
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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">[***], Roche will [***], and the license fee set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.3</u></font> will be [***].</font></div>
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      <div><br>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">The milestone provisions of <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 9.4</u></font>
          and <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 9.5</u></font> and the royalty provisions of <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 9.7</u></font> will [***].</font></div>
      <div><br>
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          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3328ac53ff6d484685bfe953762babc0">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Consequences of Termination or Expiration of the Agreement</u></font>.</font></div>
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      <div><br>
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      <div style="text-align: justify;">
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                <td style="width: 36pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.4.1.</font></td>
                <td style="vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>In General</u></font>. If this Agreement is terminated by a Party in accordance with
                      <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.12</u></font> or this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 13</u></font> in its entirety or on a country-by-country or
                      Product-by-Product basis at any time and for any reason, the following terms will apply to any such termination:</font></div>
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      <div><br>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z59289e8233b04287a8d15e1bd020508c">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Return of Information and Materials</u></font>. After termination of the Agreement,
                      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>
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      <div><br>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zaf28b3f8ac6f4901838217b407b9a863">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>License Termination</u></font>. Upon termination but not expiration of the Agreement,
                      except for the licenses granted under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font> or, if applicable, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.1</u></font>,
                      any licenses granted by Ionis to Roche under this Agreement will terminate and Roche, its Affiliates and Sublicensees will cease selling all Products that are the subject of such termination, unless Ionis elects to have Roche continue
                      to sell the applicable Product(s) as part of the Transition Activities under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.2(i)</u></font>.</font></div>
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        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">48</font></div>
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            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7f7296cb1d2e40d0a946fccaef4e1f51">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Exclusivity Covenants</u></font>. Upon termination of this Agreement for any reason
                      or expiration of this Agreement, neither Party will have any further obligations under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font> of this Agreement.</font></div>
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      <div style="text-align: justify;">
        <div>
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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development Plan</u></font>. Upon termination of this Agreement for any reason or
                      expiration of this Agreement, neither Party will have any further obligations under the Development Plan or IDCP.</font></div>
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      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zee01003f22f34e12ba5a1fe89a6b31a8">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Accrued Rights</u></font>.<font style="font-size: 10pt; font-family: 'Times New
                        Roman'; font-weight: bold;">&#160;</font>Termination of this Agreement for any reason or expiration of this Agreement will be without prejudice to any rights or financial compensation that will have accrued to the benefit of a Party
                      prior to such termination. Such termination will not relieve a Party from obligations that are expressly indicated to survive the termination of this Agreement. For purposes of clarification, milestone payments under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 9</u></font> accrue as of the date the applicable Milestone Event is achieved even if the payment is not due at that time.</font></div>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5e259edcd1fa46bf9bc211114074d973">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Survival</u></font>. The following provisions of this Agreement will survive the
                      expiration or termination of this Agreement: <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font> (Cross Licenses under Collaboration Intellectual Property); <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 7.1.4(d)</u></font> (Effect of Termination on Sublicenses), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2</u></font> (Technology Transfer) (but only to the
                      extent necessary to satisfy the requirements of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.2</u></font>), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.9</u></font>
                      (Reverse Royalty Payments to Roche for a Discontinued Product), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.11.5</u></font> (Records Retention), <font style="font-size: 10pt; font-family: 'Times New
                        Roman';"><u>Section 9.12</u></font> (Audits), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.1.1</u></font> (Ionis Intellectual Property and Roche Intellectual Property), <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 10.1.2</u></font> (Agreement Intellectual Property), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.2</u></font> (Discontinued Product), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4</u></font> (Disclaimer), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 12</u></font> (Indemnification; Insurance), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.1</u></font> (Agreement Term; Expiration), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4</u></font> (Consequences of Expiration
                      or Termination of the Agreement), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 14</u></font> (Confidentiality), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 15</u></font>
                      (Miscellaneous) and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 1</u></font> (Definitions) (to the extent definitions are embodied in the foregoing listed Articles and
                      Sections).</font></div>
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      </div>
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          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z21f8782b3ab04e7ca38a2b0857278fdd">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">13.4.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Special Consequences of Expiration or Termination of the Agreement</u></font>. If (A)
                      this Agreement expires due to the expiration of Roche&#8217;s Option under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2</u></font>, (B) Roche terminates the Agreement under <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 13.2.1</u></font> (Roche&#8217;s Termination for Convenience), or (C) Ionis terminates this Agreement under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.12</u></font>
                      (No Challenge), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.2(b)</u></font> (Ionis&#8217; Right to Terminate) or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.2.3(b)</u></font>
                      (Remedies for Failure to Use Commercially Reasonable Efforts), then, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">[***]</font> the following additional terms will also apply:</font></div>
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          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbdca3805049a447bbac247dbcd1f3798">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>License to Ionis for Discontinued Products</u></font>. Roche will
                      and hereby does grant to Ionis a sublicensable, worldwide, exclusive license or sublicense, as the case may be, under all Roche Collaboration Intellectual Property created pursuant to activities under this Agreement (excluding
                      Companion Diagnostic IP) as of the date of such reversion that Covers Discontinued Products 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>
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        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">49</font></div>
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          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z59972d4833b448c88d1985947472c273">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>License to Ionis for Companion Diagnostic Products</u></font>.
                      Roche will make available to Ionis, on commercially reasonable terms, (i) any Discontinued Product-specific diagnostic products and/or services offered by Roche as of the date of such reversion to patients who use the Discontinued
                      Product (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Companion Diagnostic Product</font>&#8221;) and (ii) any Patent Rights and Know-How Covering such Companion Diagnostic
                      Products (such intellectual property, &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 continue to Commercialize such Companion Diagnostic Products;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3a2d7987311a4c0a8a4d69b71c9048e5">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Know-How Transfer</u></font>. Within ninety (90) days following
                      the date of termination, Roche will transfer to Ionis for use with respect to the Development and Commercialization of Discontinued Products, copies of any Collaboration Know-How data, results, and regulatory information, and to the
                      extent solely related to the Discontinued Products, pricing and market access strategy information, health economic study information, material communications with payors, 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 <font style="font-size: 10pt; font-family: 'Times New
                        Roman';"><u>Section 7.2</u></font>;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z78c66eb48dcc4a388ed90ae67a5df3ca">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Regulatory Materials</u></font>. Within ninety (90) days
                      following the date of the termination, Roche will assign, and hereby does assign, to Ionis all of Roche&#8217;s right, title and interest in and to all Regulatory Materials for the Discontinued Product, including any IND, orphan drug
                      designation and marketing authorizations that relate to the applicable Discontinued Product;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8423945af07e4cebb5992284d0680aa6">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Trademarks</u></font>. Roche will license to Ionis any trademarks
                      that are specific to Discontinued Products solely for use with such Discontinued Products; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that in no event will Roche have
                      any obligation to license to Ionis 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;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z20a65c4741514db3a859c9d31c32de38">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Prosecution and Maintenance</u></font>. Ionis 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 Ionis with (and will instruct its counsel to provide Ionis 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>
      </div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">50</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5fed6b2f05924be89baae8aa964b292c">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(g)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Stocks of API and Finished Drug Product</u></font>. Ionis will
                      have the right to purchase from Roche any or all of the inventory of API and/or Finished Drug Product for such Discontinued Product held by Roche as of the effective date of termination (that are not committed to be supplied to any
                      Third Party or Sublicensee, in the ordinary course of business, as of the effective date of termination), if any, at a price equal to [***] to acquire or manufacture such inventory. Ionis will notify Roche within forty-five (45) days
                      after the effective date of termination whether Ionis elects to exercise such right;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zefdd35582d8d4cf38e6467cca8175b11">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(h)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Manufacturing Technology Transfer</u></font>. If Roche or Roche&#8217;s
                      CMO is manufacturing API and/or Finished Drug Product as of the termination triggering this provision, Ionis may request Roche to conduct (or cause to be conducted by Roche&#8217;s CMO) a technology transfer to Ionis (or Ionis&#8217; designated
                      Third Party supplier) of any technology, information and data reasonably related to Roche&#8217;s or such CMO&#8217;s manufacturing and supply of API and/or Finished Drug Product for such Discontinued Product, and if so requested, Roche will
                      conduct (or cause to be conducted by Roche&#8217;s CMO) such a technology transfer, and Ionis will [***], and Roche will (or will cause Roche&#8217;s CMO to) continue to (i) provide reasonable support and cooperation with Ionis&#8217; regulatory
                      filings and interactions with Regulatory Authorities related to Roche&#8217;s or such CMO&#8217;s API and/or Finished Drug Product manufacturing (including any required inspections), and (ii) supply (or cause to be supplied by Roche&#8217;s CMO) API
                      and/or Finished Drug Product to Ionis, at a price equal to [***] to enable Ionis to identify and contract with a suitable Third Party API and/or Finished Drug Product manufacturer; and</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zca49b225dd484ea2a2a3cd29e8537cc5">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Transition Activities</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-indent: 108pt;">
        <div>
          <div style="text-align: left;"><font style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">For </font></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">a period of up to
              [***] following the effective date of termination:</font></div>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdbb05e46d20f44a9849816aa1110515e">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Parties wish to provide a mechanism to ensure that, assuming the Discontinued Product is available to patients as of the reversion date, patients who were being
                      treated with the Discontinued Product prior to such termination or who desire access to the Discontinued Product can continue to have access to such Discontinued Product while the regulatory and commercial responsibilities for the
                      Discontinued Product are transitioned from Roche to Ionis. As such, Ionis may request Roche to perform transition activities that are necessary or useful to (1) transition Roche&#8217;s Commercialization activities (if any) to Ionis to
                      minimize disruption to sales, (2) provide patients with continued access to the applicable Discontinued Products (if applicable), (3) enable Ionis (or Ionis&#8217; designee) to assume and execute the responsibilities under all Approvals and
                      ongoing Clinical Studies for the applicable Discontinued Product, and (4) ensure long-term continuity of supply for the Discontinued Product (collectively, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
                        font-weight: bold; font-style: italic;">Transition Activities</font>&#8221;), including, if applicable, the categories of services and deliverables listed on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant:
                        small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>13.4.2(i)</u></font>, but no longer than [***] following the effective date of termination. If applicable, Roche will perform
                      such Transition Activities using commercially reasonable efforts for the periods set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size:
                        10pt; font-family: 'Times New Roman';"><u>13.4.2(i)</u></font>; provided Roche and Ionis may mutually agree in writing to conduct the Transition Activities for a longer period of time.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">51</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6e8744082bee4c918a9d0c008df90273">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis may elect to have Roche perform the applicable Transition Activities by providing written notice to Roche no later than forty-five (45) days following the effective
                      date of the termination. If Ionis requests Transition Activities, without limiting the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.2</u></font>, the Parties will mutually agree upon a
                      transition plan for Roche to perform the applicable Transition Activities including delivery and transition dates. In addition, the Parties will establish a transition committee consisting of at least each Party&#8217;s Alliance Managers, a
                      representative from each Party&#8217;s chemistry, manufacturing and controls (CMC) group who was responsible for the Discontinued Product prior to the termination, and up to two (2) additional representatives from each Party who are from
                      other relevant functional groups to facilitate a smooth transition. While Roche is providing applicable Transition Activities, Roche and Ionis will agree on talking points and a communication plan to customers, specialty pharmacies,
                      physicians, regulatory authorities, patient advocacy groups, and clinical study investigators, in each case only if applicable at the time of reversion, and Roche will make all such communications to such applicable entities in
                      accordance with the mutually agreed talking points.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z40058f462f3148b286f8eda62236f8ad">

              <tr>
                <td style="width: 108pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will [***] to perform the Transition Activities. In addition, Ionis will [***] to perform the Transition Activities. Ionis will own [***].</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">ARTICLE 14.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">CONFIDENTIALITY</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6645d1c21d02455bbd37b7433cb31b71">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Confidentiality; Exceptions</u></font>. Except to the extent expressly authorized by
                      this Agreement or otherwise agreed in writing, the Parties agree that, during the Agreement Term and for five years thereafter, the receiving Party (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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="font-size: 10pt; font-family: 'Times New Roman';">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-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Confidential Information</font>&#8221;).</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">52</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z866b048d96d442e7aac270e8e880c3af">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Prior Confidentiality Agreement</u></font>. The Non-Disclosure Agreement executed by
                      Ionis and Roche on February 7, 2018 (including any and all amendments thereto) (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">CDA</font>&#8221;) will terminate as of the Effective
                      Date. All Confidential Information exchanged between the Parties under the CDA and on or after the Effective Date under this Agreement will be subject to the terms of this <font style="font-size: 10pt; font-family: 'Times New
                        Roman';"><u>ARTICLE 14</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7090ea9d97a2427c8160bee781f88c2e">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Authorized Disclosure</u></font>. 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-size: 10pt; font-family: 'Times New Roman'; 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 14.4</u></font> below), complying with applicable governmental regulations, obtaining Approvals, conducting
                      Non-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-size: 10pt;
                        font-family: 'Times New Roman'; 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>
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        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za55cc6af33574b62817e74f69b8de28c">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Press Release; Publications; Disclosure of Agreement</u></font>.</font></div>
                </td>
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        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd4ba4bff8dc84ef89a15b1b910cd79a1">

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                <td style="width: 36pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.4.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Public Announcements &#8211; Generally</u></font>. Upon execution of this Agreement, Ionis
                      may issue a 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 14.4</u></font>, 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>
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      <div><br>
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        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">53</font></div>
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            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbad423877e254ec5aa3cfd371f1a2233">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.4.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Use of Name</u></font>.<font style="font-size: 10pt; font-family: 'Times New Roman';
                        font-weight: bold;">&#160;</font>Except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 14.4.9</u></font>, 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>
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          </table>
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      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z16522b8a411e47f291de5e3c4b815324">

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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.4.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Notice of Significant Events</u></font>. Each Party will notify (no later than three
                      (3) 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 14.4.1</u></font> 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 (3) Business Days in advance of such proposed public
                      disclosure, which approval will not be unreasonably withheld or delayed.</font></div>
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      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zeae0b116f8494551a392cd803a93c6e2">

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                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.4.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Before Option Exercise</u></font>. Before Option exercise, Ionis 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 IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to the public; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>, that with respect to any proposed press release or other similar public
                      communication by Ionis disclosing regulatory discussions, the efficacy or safety data <font style="font-size: 10pt; font-family: 'Times New Roman';">or</font> clinical results related to IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>, (i) Ionis will submit such proposed communication to Roche for review at least two (2) 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) Ionis will in good faith consider any changes that are timely recommended by Roche.</font></div>
                </td>
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      </div>
      <div><br>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z54906abb7667411e90cd37617988b7c1">

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                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.4.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>After Option Exercise</u></font>. 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 IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> to the public; <font style="font-size: 10pt; font-family: 'Times New Roman'; 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="font-size: 10pt; font-family: 'Times New Roman';">or</font> results related to the Products or Roche&#8217;s sales projections, (i) Roche
                      will submit such proposed communication to Ionis for review at least two (2) Business Days in advance of such proposed public disclosure, (ii) Ionis 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 Ionis.</font></div>
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        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">54</font></div>
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          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z640209bd5fc2407d9f99fc85208fdc05">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.4.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Scientific or Clinical Presentations</u></font>. Regarding any proposed scientific
                      publications related to results from any Clinical Studies regarding Products, 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 JPC 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 the Development Plan or IDCP. 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>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze0e91fbce3364efb83b1be50ef22550f">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.4.7.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>SEC Filings</u></font>. 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>
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        </div>
      </div>
      <div><br>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc82506d8cc0d4df79858b4baea1807fb">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.4.8.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Subsequent Disclosure</u></font>. 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>
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        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbc38cbdc249d45e3bdfd19c5cdc22ff8">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">14.4.9.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Acknowledgment; Commercial Materials</u></font>. Each Party will acknowledge in any
                      press release, public presentation, publication or commercial marketing materials regarding the Collaboration or a Product, the other Party&#8217;s role in discovering and developing a Product or Discontinued Product, as applicable, that
                      the Product is under license from Ionis and otherwise acknowledge the contributions from the other Party, and each Party&#8217;s stock ticker symbol (e.g., Ionis: Nasdaq: IONIS; Roche: SIX: RO, ROG; OTCQX: RHHBY). Ionis may include the
                      Products (and identify Roche as its partner for the Product) in Ionis&#8217; drug pipeline. In addition, subject to Applicable Law, the words &#8220;Discovered and developed by Ionis Pharmaceuticals&#8221; will be included and reasonably visible in
                      Product communications and branding, provided that Roche will have final decision-making authority regarding the applicability of any legal and regulatory requirements for such acknowledgement.</font></div>
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      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"> <br>
        </font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">ARTICLE 15.</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">MISCELLANEOUS</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Dispute Resolution</u></font>.</font></div>
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      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.1.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Escalation</u></font>. 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.2</u></font>), either
                      Party may request in writing that the dispute be referred for resolution to the Head of Roche Partnering of Roche and the Chief Operating Officer of Ionis (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
                        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, except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)(ii)</u></font>, the dispute will be referred to binding arbitration under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.1.2</u></font>.</font></div>
                </td>
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      </div>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z118a95385924460393d6eef4ec104833">

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                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.1.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Binding Arbitration</u></font>. If a dispute subject to <font style="font-size:
                        10pt; font-family: 'Times New Roman';"><u>Section 15.1.1</u></font> is not resolved pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.1.1</u></font>, such dispute will be resolved through
                      binding arbitration in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.1.2</u></font> and under the Commercial Arbitration Rules of the American Arbitration Association (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">AAA</font>&#8221;) then in effect, including application of the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 arbitrators 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, U.S. and will be conducted by three arbitrators. Each of Roche and Ionis will appoint one
                      (1) arbitrator within thirty (30) days after the notice that initiated the arbitration. These two (2) arbitrators will 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>
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      <div><br>
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      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6ac812e667f745bbb78b54544c78eed4">

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                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Governing Law; Jurisdiction; Venue; Service of Process</u></font>.</font></div>
                </td>
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      <div><br>
      </div>
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        <div>
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                <td style="width: 36pt;">&#160;</td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.2.1.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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., without reference to conflicts
                      of laws principles.</font></div>
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                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.2.2.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.7</u></font>, 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.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">56</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z163d6ce995804913a18a2a57ead6040d">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.3.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Remedies</u></font>. 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.2</u></font>). Except
                      for the offsets and credits explicitly set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.10.3(b)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.12</u></font>,
                      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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc54c39fe0b6844209807b0bd34afe088">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.4.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Assignment and Successors</u></font>. Neither this Agreement nor any obligation of a
                      Party hereunder may be assigned by either Party without the consent of the other, 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-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Non-Transferring Party</font>&#8221;) under <font style="font-size: 10pt; font-family:
                        'Times New Roman';"><u>ARTICLE 9</u></font> for the taxes withheld such that the Non-Transferring Party receives [***] assignment. In addition, Ionis 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 <font style="font-size: 10pt;
                        font-family: 'Times New Roman';"><u>Section 15.4</u></font> will be null and void.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">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 <font style="font-size: 10pt; font-family:
            'Times New Roman';"><u>Section 15.4</u></font>, 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&#8217;s Annual tax returns (federal and state) and, in years in which the Non-Transferring Party utilizes the [***], supporting documentation for such [***].</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7ca7e306d5634cc7bfda9be6434dcd8a">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.5.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Change of Control</u></font>. If Ionis undergoes a Change of Control, then Roche will
                      have the right at any time after it exercises the Option to disband the JSC and make unilateral decisions with respect to the Development Plan, IDCP, Development and Commercialization with no obligation to seek input from Ionis or its
                      successor, if applicable.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">57</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z726f3a2e2b2d4263a33fbc7a49882b89">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.6.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Force Majeure</u></font>. 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. To the extent possible, each Party will use
                      reasonable efforts to minimize the duration of any force majeure.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z05b1d0030af945a3b934601512b98250">

              <tr>
                <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.7.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Notices</u></font>. Any notice or request required or permitted to be given under or
                      in connection with this Agreement will be deemed to have been sufficiently given if in writing and personally delivered or sent by certified mail (return receipt requested), 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>
      </div>
      <div><br>
      </div>
      <div>
        <div style="text-align: left;">
          <div>
            <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5d3fb98c23814c0181ea86b1666698cb">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 144pt; vertical-align: top; align: right; font-family: 'Times New Roman'; font-size: 10pt;">If to Ionis, addressed to:</td>
                  <td style="width: auto; vertical-align: top; text-align: left;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis Pharmaceuticals, Inc.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">2855 Gazelle Court</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Carlsbad, CA&#160; 92010</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Attention:&#160; Chief Operating Officer</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Fax:&#160; [***]</font></div>
        <div><br>
        </div>
        <div style="text-align: left;">
          <div>
            <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z68cbc46d912e4df9af0445e75ae4c284">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 144pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">with a copy to:</font></td>
                  <td style="width: auto; vertical-align: top; text-align: left;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis Pharmaceuticals, Inc.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">2855 Gazelle Court</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Carlsbad, CA&#160; 92010</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Attention:&#160; General Counsel</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Email: [***]</font></div>
        <div><br>
        </div>
        <div style="text-align: left;">
          <div>
            <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1e64f1f753eb461581008df7823a68a0">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 144pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">If to Roche, addressed to:</font></td>
                  <td style="width: auto; vertical-align: top; text-align: left;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">F. Hoffmann-La Roche Ltd</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Grenzacherstrasse 124</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">4070 Basel, Switzerland</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Attention:&#160; Corporate Legal Department</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Fax:&#160; [***]</font></div>
        <div><br>
        </div>
        <div style="text-align: left;">
          <div>
            <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6aed157317604f7b959e0c07bed4e287">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 144pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">If to Roche, addressed to:</font></td>
                  <td style="width: auto; vertical-align: top; text-align: left;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Hoffmann-La Roche Inc.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">150 Clove Road, Suite 8</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Little Falls, NJ 07424</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Attention:&#160; Corporate Secretary</font></div>
        <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Fax:&#160; [***]</font></div>
      </div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">58</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div>
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
        </div>
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">
          <div style="text-align: left;">
            <div>
              <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z400ba50076054980ac94aac54a334e53">

                  <tr>
                    <td style="width: 36pt;"><br>
                    </td>
                    <td style="width: 144pt; vertical-align: top; align: right; font-family: 'Times New Roman'; font-size: 10pt;">with a copy to:</td>
                    <td style="width: auto; vertical-align: top; text-align: left;">
                      <div><font style="font-size: 10pt; font-family: 'Times New Roman';">F. Hoffmann-La Roche Ltd</font></div>
                    </td>
                  </tr>

              </table>
            </div>
          </div>
          <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Grenzacherstrasse 124</font></div>
          <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">4070 Basel, Switzerland</font></div>
          <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Attention:&#160; Alliance Manager</font></div>
          <div style="text-align: left; margin-left: 180pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Fax:&#160; [***]</font></div>
          <br>
        </div>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">or to such other address for such Party as it will have specified by like notice to the other Party; <font style="font-size: 10pt;
            font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc987fd6c070c452a9a6fbcadbb737173">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.8.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Invoices</u></font>.&#160; All invoices that are required or permitted hereunder will be
                      in writing and sent by Ionis to Roche at the following address or any other address that Roche may later provide:</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">F. Hoffmann-La Roche AG</font></div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Kreditorenbuchhaltung</font></div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">4070 Basel</font></div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Switzerland</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">with an electronic copy to Roche&#8217;s Alliance Manager.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Upon Ionis&#8217; request, Roche&#8217;s Alliance Manager will provide Ionis&#8217; Alliance Manager with any additional information reasonably
          requested by Ionis to facilitate the prompt delivery of invoices to Roche, including a facsimile number for sending invoices.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8618f67a689a4e61bd698820b9247a9e">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.9.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Export Clause</u></font>. 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6fe3774d43814d278baa348a2dd88ea0">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.10.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Waiver</u></font>. Neither Party may waive or release any of its rights or interests
                      in this Agreement except in writing.&#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>
      </div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">59</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb5ded29ac78f409c9048f2abc3b575a8">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.11.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Severability</u></font>. 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z066c6e85c09443dc9ad6e3ba7b4ed4c4">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.12.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Entire Agreement</u></font>. This Agreement, together with the Schedules and
                      Appendices hereto, sets forth all the covenants, promises, agreements, warranties, representations, conditions and understandings between the Parties regarding the subject matter hereof and supersedes and terminates all prior
                      agreements and understandings between the Parties pertaining to the subject matter hereof. There are no covenants, promises, agreements, warranties, representations, conditions or understandings, either oral or written, between the
                      Parties regarding the subject matter hereof other than as set forth in this Agreement and the Schedules and Appendices hereto.&#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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z54bfc4c9e72d4ebcaa37777a7baae92d">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.13.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Independent Contractors</u></font>. Nothing herein will be construed to create any
                      relationship of employer and employee, agent and principal, partnership or joint venture between the Parties. Each Party is an independent contractor. 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z54d0ddd596c944ac8809598936ec0837">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.14.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Interpretation</u></font>. Except as otherwise explicitly specified to the contrary,
                      (a) references to a section, appendix or schedule means a section of, or appendix or schedule to this Agreement, unless another agreement is specified, (b) the word &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
                        font-style: italic;">including</font>&#8221; (in its various forms) means &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">including without limitation</font>&#8221;, (c) 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, (d) words in the singular or plural form include
                      the plural and singular form, respectively, (e) references to a particular Person include such Person&#8217;s successors and assigns to the extent not prohibited by this Agreement, (f) unless otherwise specified, &#8220;$&#8221; is in reference to
                      United States Dollars, and (g) the headings contained in this Agreement, in any appendix 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf4876c3f2fb74d31a744bb773ff0b084">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.15.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Further Actions</u></font>. Each Party will execute, acknowledge and deliver such
                      further instruments, and do all such other acts, as may be necessary or appropriate to carry out the expressly stated purposes and the clear intent of this Agreement.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z86a5cd562c06469a843308c887accdbd">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.16.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Construction of Agreement</u></font>.<font style="font-size: 10pt; font-family:
                        'Times New Roman'; 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>
      </div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">60</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
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      </div>
      <div style="text-align: justify;">
        <div>
          <div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
            <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;"> <br>
            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6711935b7eca4ddcbc3b438399e53a7a">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.17.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Supremacy</u></font>. 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z52ed44c7b5e24fd99ddf76d730900d1e">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">15.18.</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Counterparts</u></font>. 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>
      </div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;">[SIGNATURE PAGES FOLLOW]</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">* - * - * - *</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">61</font></div>
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      </div>
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      <div style="text-align: left;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
          </font></font></div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">IN WITNESS WHEREOF</font>, 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: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="z89010f06ef894afa94ded1e93df3103b">

          <tr>
            <td colspan="3" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">F. Hoffmann-La Roche Ltd</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">&#160;</td>
            <td style="width: 35%; vertical-align: top;">&#160;</td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">By:</font></div>
            </td>
            <td style="width: 2%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td style="width: 35%; vertical-align: top; border-bottom: 2px solid black;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">/s/ Stefan Arnold</font></font></div>
            </td>
            <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Name:</font></div>
            </td>
            <td style="width: 35%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Stefan Arnold</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Title:</font></div>
            </td>
            <td style="width: 35%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Head Legal Pharma</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">&#160;</td>
            <td style="width: 35%; vertical-align: top;">&#160;</td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">By:</font></div>
            </td>
            <td style="width: 2%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td style="width: 35%; vertical-align: top; border-bottom: 2px solid black;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">/s/ Vikas Kabra</font></font></div>
            </td>
            <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Name:</font></div>
            </td>
            <td style="width: 35%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Vikas Kabra</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Title:</font></div>
            </td>
            <td style="width: 35%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Head of Transaction Excellence</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">Signature Page to FB Development Collaboration, Option and License Agreement</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">62</font></div>
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      <div style="text-align: left;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"> <br>
          </font></font></div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">IN WITNESS WHEREOF</font>, 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: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="zb65be2d71c67438caa824f1aaf3bba59">

          <tr>
            <td colspan="3" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">Hoffmann-La Roche Inc.</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">&#160;</td>
            <td style="width: 35%; vertical-align: top;">&#160;</td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">By:</font></div>
            </td>
            <td style="width: 2%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td style="width: 35%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">/s/ John Parise</font></font></div>
            </td>
            <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Name:</font></div>
            </td>
            <td style="width: 35%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">John Parise</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Title:</font></div>
            </td>
            <td style="width: 35%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Authorized Signatory</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">Signature Page to FB Development Collaboration, Option and License Agreement</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">63</font></div>
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      </div>
      <div style="text-align: justify;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
          </font></font></div>
      <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">IN WITNESS WHEREOF</font>, 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" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="zea24c365049448c59126df06ac0b3570">

          <tr>
            <td colspan="3" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">Ionis Pharmaceuticals, Inc.</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">&#160;</td>
            <td style="width: 35%; vertical-align: top;">&#160;</td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">By:</font></div>
            </td>
            <td style="width: 2%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
            <td style="width: 35%; vertical-align: top; border-bottom: 2px solid black;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">/s/ Stanley T. Crooke</font></font></div>
            </td>
            <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Name:</font></div>
            </td>
            <td style="width: 35%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Stanley T. Crooke</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>
          <tr>
            <td colspan="2" style="vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Title:</font></div>
            </td>
            <td style="width: 35%; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Chief Executive Officer</font></div>
            </td>
            <td style="width: 60%; vertical-align: top;">&#160;</td>
          </tr>

      </table>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">Signature Page to FB Development Collaboration, Option and License Agreement</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;">64</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
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      </div>
      <div style="text-align: left;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>List of Appendices and
              Schedules</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 1</u></font> &#8211; Definitions</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 2</u></font> &#8211; Specific Performance Milestone Events</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font> &#8211; Permitted Licenses as of the
          Effective Date</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 4.2</u></font><font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-variant: small-caps;">&#160;</font>&#8211; Alliance Management Activities</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 4.4.2</u></font><font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-variant: small-caps;">&#160;</font>&#8211; Ionis&#8217; Fully Absorbed Cost of Goods Methodology</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family:
            'Times New Roman';"><u>9.7.2(e)</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"> &#8211; </font>Royalty Calculation Examples</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family:
            'Times New Roman';"><u>9.7.2(f)</u></font> &#8211; Allocation of Net Sales</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family:
            'Times New Roman';"><u> 11.2.4(a)</u></font> &#8211; Ionis Core Technology Patents</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family:
            'Times New Roman';"><u> 11.2.4(b)</u></font> &#8211; Ionis Manufacturing and Analytical Patents</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family:
            'Times New Roman';"><u> 11.2.4(c)</u></font> &#8211; Ionis Product-Specific Patents</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family:
            'Times New Roman';"><u> 11.2.6</u></font> &#8211; Prior Agreement</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family:
            'Times New Roman';"><u> 13.4.2(i)</u></font> &#8211; Transition Activities</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">65</font></div>
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      </div>
      <div style="text-align: left;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Appendix 1</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">DEFINITIONS</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For purposes of this Agreement, the following capitalized terms will have the following meanings:</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">&#8220;<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">AAA</font>&#8221; has the meaning
          set forth in <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 15.1.2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">&#8220;<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">Acceptance of Filing</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-size: 10pt;
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          received from European Regulatory Authorities; <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;">provided that</font> if the centralized filing procedure is not used, then Acceptance of Filing will be
          determined upon the validation of such MAA by the applicable Regulatory Authority in a Major Market in Europe, and (c) in Japan, receipt of written notice of acceptance of filing of such JNDA from the Koseisho (<font style="font-size: 10pt;
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      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">&#8220;<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">Additional Core IP</font>&#8221; has
          the meaning set forth in <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 9.10.3(a)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">&#8220;<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">Additional Ionis In-License
            Agreements</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 9.10.1(a)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">&#8220;<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">Additional Product-Specific
            Patents</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 9.10.2(a)</u></font>.</font></div>
      <div><br>
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      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">&#8220;<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; 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. Anything to the contrary in this paragraph notwithstanding, Chugai Pharmaceutical Co., Ltd, a Japanese corporation (&#8220;<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight:
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          and/or its subsidiaries (if any), will not be deemed an Affiliate of Roche unless Roche provides written notice to Ionis of its desire to include Chugai and/or FMI as an Affiliate of Roche.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Agreement</font>&#8221; has the meaning set forth in the
          Preamble of this Agreement.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Agreement</font>&#160;<font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Term</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Alliance Manager</font>&#8221; has the meaning set forth
          in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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).</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">66</font></div>
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      </div>
      <div style="text-align: justify;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">API</font>&#8221; means the bulk active pharmaceutical
          ingredient manufactured in accordance with cGMP (unless expressly stated otherwise) for a Product.</font></div>
      <div><br>
      </div>
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            10pt; font-family: 'Times New Roman'; 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
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      <div><br>
      </div>
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          reimbursement approval, in such jurisdiction in accordance with Applicable Laws, or (B) the First Commercial Sale of a Product in the EU or in a European country in a Major Market; and (ii) with respect to a Product in any regulatory jurisdiction
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      <div><br>
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      <div><br>
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      <div><br>
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      <div><br>
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      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Business Day</font>&#8221; means any day other than a
          Saturday or Sunday on which banking institutions in both New York, New York and Zurich, Switzerland are open for business.</font></div>
      <div><br>
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      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
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      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">CDA</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 14.2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">67</font></div>
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Chugai</font>&#8221; has the meaning set forth in the
          definition of Affiliate.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Claims</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Clinical Study</font>&#8221; or &#8220;<font style="font-size:
            10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaboration</font>&#8221; means the conduct of the
          Development Plan in accordance with this Agreement.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaboration Intellectual Property</font>&#8221; means
          collectively Ionis Collaboration Intellectual Property and Roche Collaboration Intellectual Property.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Commercialize</font>&#8221;, &#8220;<font style="font-size:
            10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Commercialization</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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) Ionis, with respect to a Discontinued Product that is being Developed and Commercialized by or on
          behalf of Ionis, its Affiliates or Sublicensees hereunder.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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. 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 activities assigned to Roche set forth in the Development Plan or IDCP in accordance with the timelines set forth therein, (ii) perform the &#8220;<font style="font-size: 10pt; font-family: 'Times New
            Roman'; font-style: italic;">General Activities</font>&#8221; set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>
              2</u></font>, and (iii) achieve the specific performance milestone events set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix</u></font><font style="font-size: 10pt; font-family:
            'Times New Roman';"><u> 2</u></font> (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Specific Performance Milestone Events</font>&#8221;) for a Product on the timeline set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 2</u></font>; and (B) Commercially Reasonable Efforts as it applies to
          Ionis&#8217; Development of IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> hereunder includes use of Commercially Reasonable Efforts to perform the activities assigned to Ionis under the Development Plan in
          accordance with the timelines set forth therein and the Specific Performance Milestone Events set forth in<font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u> Appendix</u></font><font style="font-size:
            10pt; font-family: 'Times New Roman';"><u> 2</u></font>; provided, however, in each case, if regulatory or Development issues arise that are outside of either Party&#8217;s reasonable control and make achievement of any Specific Performance Milestone
          Event on the stated timeline impossible, the Parties will meet and negotiate in good faith to revise, consistent with any applicable Additional Ionis In-License Agreements, the date by which the applicable Specific Performance Milestone Event
          must be achieved. 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.</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">68</font></div>
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      </div>
      <div style="text-align: justify;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Companion Diagnostic IP</font>&#8221; has the meaning
          set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.2(b)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Companion Diagnostic Product</font>&#8221; has the
          meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.2(b)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competitive Infringement</font>&#8221; has the meaning
          set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.5.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Complete</font>&#8221; or &#8220;<font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Completion</font>&#8221; means, with respect to a Clinical Study, the point in time at which the primary database lock for such study has occurred and, if such study has a
          statistical analysis plan, the listing and tables of safety and efficacy data generated based on that primary database lock under the statistical analysis plan for such study are available.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Compound</font>&#8221; means an ASO that is designed to
          bind to the RNA that encodes Factor B where such ASO is discovered by Ionis prior to or in the performance of the Development Plan.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Compulsory Sublicensee</font>&#8221; means a Third Party
          that was granted a Compulsory Sublicense.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Confidential Information</font>&#8221; has the meaning
          set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 14.1</u></font>. &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Confidential Information</font>&#8221; does not include
          information that:</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2e12062a066c44e2baccce59d1b37b94">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z85a4bbe08f364d9ba9515df8d53a025a">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc48d9f0449144d788ebee8407b6b8b80">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc64d2258bd9c4dad96324424bc35fe0c">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">69</font></div>
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      </div>
      <div style="text-align: justify;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Conjugate Technology</font>&#8221; means a group of
          atoms covalently bound to an oligonucleotide designed to enhance one or more properties of the oligonucleotide, such as targeting of antisense drugs to specific tissues and cells.&#160; Conjugate Technology includes N-acetylgalactosamine (GalNAc)
          ligand conjugates capable of binding to the asialoglycoprotein receptor (ASGP-R) and enhancing the targeting of antisense drugs.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Control</font>&#8221;,&#160; &#8220;<font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Controlled</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Controlling</font>&#8221;<font style="font-size:
            10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">&#160;</font>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-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Third Party Compensation</font>&#8221;) (other than Ionis Supported
          Pass-Through Costs in the case of Ionis, 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-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Cover</font>&#8221;, &#8220;<font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Covered</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Develop</font>,&#8221; &#8220;<font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Developing</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Development</font>&#8221; means with respect to a
          Product, any and all discovery, characterization, or non-clinical (including non-clinical studies required to file an IND), 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 non-clinical and clinical activities and Approval), including human clinical trials conducted after Approval of a Product to seek Approval for additional Indications for a Product.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Development Plan</font>&#8221; has the meaning set forth
          in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Development Program</font> has the meaning set
          forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Disclosing Party</font>&#8221; has the meaning set forth
          in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 14.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Discontinued Product</font>&#8221; means a Product that
          is the subject of a termination under this Agreement.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Effective Date</font>&#8221; has the meaning set forth
          in the Preamble of this Agreement.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">EMA</font>&#8221; means the European Medicines Agency
          and any successor entity thereto.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">European Union</font>&#8221; or &#8220;<font style="font-size:
            10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">EU</font>&#8221; means each and every country or territory that is officially part of the European Union.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Executives</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.1.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Existing Diagnostic Agreement</font>&#8221; means that
          certain Non-Exclusive G-Clamp License Agreement between Isis (now Ionis) and F. Hoffmann-La Roche Ltd dated April 26, 2011.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Factor B</font>&#8221; means the human gene complement
          factor B (GenBank accession # NM_001710; Gene ID: 629), or any alternative splice variants, mutants, polymorphisms and fragments thereof.</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">70</font></div>
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      <div style="text-align: justify;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">FDA</font>&#8221; means the United States Food and Drug
          Administration and any successor entity thereto.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">FDCA</font>&#8221; will mean the United States Food,
          Drug and Cosmetics Act.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Field</font>&#8221; means the prophylactic, therapeutic
          and diagnostic use or form of administration of a Product for any Indication.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Finished Drug Product</font>&#8221; means any drug
          product containing API as an active ingredient in finished bulk form for the Development or Commercialization of a Product by a Party under this Agreement.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">FMI</font>&#8221; has the meaning set forth in the
          definition of Affiliate.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Full Royalty Period</font>&#8221; has the meaning set
          forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2(a)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Fully Absorbed Cost of Goods</font>&#8221; means the
          costs incurred by Ionis as determined using the methodology set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New
            Roman';"><u> 4.4.2</u></font> fairly applied and as employed on a consistent basis throughout Ionis&#8217; operations.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">GA</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Generic Product</font>&#8221;<font style="font-size:
            10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>means, on a Product-by-Product and country-by-country basis, any product sold by a Third Party that is not a licensee or Sublicensee of Roche where such product(s) 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,
          and such product(s) taken in the aggregate has a market share (measured in number of prescriptions during a Calendar Quarter with the numerator of such fractional share being the Generic Products taken in the aggregate, and the denominator being
          the total of the Generic Products taken in the aggregate plus the Product taken in the aggregate, as provided by IQVIA) in such country of at least [***].</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Group Sublicensee</font>&#8221; means any individual,
          corporation, association or other business entity:</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb0e6476c930b4dca9593d3d6905b7458">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">to which Roche has granted a Sublicense;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3d568b9f73f3432fb4ff5fe23fa7910d">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">that is not an Affiliate of Roche; and</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0569f172c37e44cabb1cbd8503b47ac6">

              <tr>
                <td style="width: 36pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">that is consolidated within Roche&#8217;s externally published audited financial statements.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">gRED</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1.2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">71</font></div>
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">IDCP</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.1.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">[***]</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Indemnitee</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.3</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Indication</font>&#8221; means a primary sickness or
          medical condition or any interruption, cessation or disorder of a particular bodily function, system or organ (each a &#8220;disease&#8221;) including sub-types and pediatric populations of the same disease.&#160; Indications that require separate pivotal trials
          to obtain Approval to market and sell a Product are separate Indications.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Initiation</font>&#8221; means, with respect to any
          Clinical Study, dosing of the first human subject in such Clinical Study.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis</font>&#8221; has the meaning set forth in the
          Preamble of this Agreement.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Collaboration Know-How</font>&#8221; means
          Know-How discovered, developed, invented or created solely by or on behalf of Ionis or its Affiliate or a Third Party acting on their behalf in the performance of the Development Plan, that is necessary or useful to Develop, Manufacture or
          Commercialize a Product in the Field.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Collaboration Patents</font>&#8221; means Patent
          Rights discovered, developed, invented or created solely by or on behalf of Ionis or its Affiliate or a Third Party acting on their behalf in the performance of the Development Plan, that are necessary or useful to Develop, Manufacture or
          Commercialize a Product in the Field.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Collaboration Intellectual Property</font>&#8221;
          means Ionis Collaboration Know-How, Ionis Collaboration Patents and Ionis&#8217; interest in any Jointly-Owned Collaboration Intellectual Property.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Core Technology Patents</font>&#8221; means all
          Patent Rights owned, used, developed by, or licensed to Ionis or its Affiliates, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term, claiming subject matter generally
          applicable to ASOs or Conjugate Technology and not limited to a single specified gene target, other than Ionis Manufacturing and Analytical Patents. <font style="font-size: 10pt; font-family: 'Times New Roman';">A list of </font>Ionis Core
          Technology Patents <font style="font-size: 10pt; font-family: 'Times New Roman';">as of the </font>Effective Date <font style="font-size: 10pt; font-family: 'Times New Roman';">is set forth on </font><font style="font-size: 10pt; font-family:
            'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 11.2.4(a)</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"> attached hereto.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">IONIS-FB-L</font><sub style="vertical-align: bottom; line-height: 1; font-size: smaller;"><font style="font-weight: bold; font-style: italic;">Rx</font></sub>&#8221; means the compound known as ISIS 696844, which has the following structure:&#160; [***].</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis&#8217; Fully Absorbed Cost of Goods</font>&#8221; means
          the costs incurred by Ionis as determined using the methodology set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New
            Roman';"><u> 4.4.2</u></font> fairly applied and as employed on a consistent basis throughout Ionis&#8217; operations.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Internal ASO Safety Database</font>&#8221; has the
          meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.2.2(a)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Know-How</font>&#8221; means any Know-How,
          including Ionis&#8217; interest in any Jointly-Owned Collaboration Know-How, owned, used, developed by, or licensed to Ionis or its Affiliates, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any time during
          the Agreement Term. Ionis Know-How does not include the Ionis Manufacturing and Analytical Know-How.</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">72</font></div>
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      </div>
      <div>
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Manufacturing and Analytical Know-How</font>&#8221;
          means Know-How, including Ionis&#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 Ionis or its
          Affiliates, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term. Ionis Manufacturing and Analytical Know-How does not include the Ionis Know-How.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Manufacturing and Analytical Patents</font>&#8221;
          means Patent Rights, including Ionis&#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 Ionis or its Affiliates, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term. A list of Ionis Manufacturing and Analytical Patents as of the Effective Date
          is set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 11.2.4(b)</u></font> attached hereto. Ionis
          Manufacturing and Analytical Patents do not include the Ionis Product-Specific Patents or the Ionis Core Technology Patents.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Product Reverse Royalties</font>&#8221; has the
          meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.9</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Product-Specific Patents</font>&#8221; means
          Product-Specific Patents Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term. A list of Ionis Product-Specific Patents as of the Effective Date is set forth on <font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 11.2.4(c)</u></font> attached hereto.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Supported Pass-Through Costs</font>&#8221; means
          the licensing costs and payments payable by Ionis to Third Parties to the extent arising from a Third Party agreement under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>[***]</u></font> or <font style="font-size: 10pt;
            font-family: 'Times New Roman';"><u>[***]</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Japan NDA</font>&#8221; or &#8220;<font style="font-size:
            10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">JNDA</font>&#8221; means<font style="font-size: 10pt; font-family: 'Times New Roman';"> the Japanese equivalent of an </font>NDA <font style="font-size: 10pt;
            font-family: 'Times New Roman';">filed with the </font>Koseisho (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">,</font> the
          Japanese Ministry of Health and Welfare, or any successor agency thereto)<font style="font-size: 10pt; font-family: 'Times New Roman';">.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
            font-style: italic;">JNDA Approval</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8221; means the </font>Approval <font style="font-size: 10pt; font-family: 'Times New Roman';">of a </font>JNDA <font style="font-size:
            10pt; font-family: 'Times New Roman';">by the </font>Koseisho<font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;</font>(<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font><font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-style: italic;">,</font> the Japanese Ministry of Health and Welfare, or any successor agency thereto) <font style="font-size: 10pt; font-family: 'Times New Roman';">for the applicable </font>Product <font style="font-size: 10pt; font-family: 'Times New Roman';">in Japan.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Joint Development Committee</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">JDC</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
            font-style: italic;">Joint Patent Committee</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8221; or &#8220;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">JPC</font>&#8221; has
          the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.1.3(a)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Joint Steering Committee</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">JSC</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 the Development 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 the Development 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Jointly-Owned Collaboration Intellectual Property</font>&#8221;
          means Jointly-Owned Collaboration Know-How and Jointly-Owned Collaboration Patents.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Key Meeting</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.1.6</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
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        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">73</font></div>
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      <div style="text-align: justify;">
        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Lead Party</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Licensed CMO</font>&#8221; has the meaning set forth in
          <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.4(a)(ii)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Licensed Know-How</font>&#8221; means Ionis
          Manufacturing and Analytical Know-How, Ionis Know-How, Ionis Collaboration Know-How, and Ionis&#8217; interest in any Jointly-Owned Collaboration Know-How. For clarity, Licensed Know-How does not include any Know-How generated after the Effective Date
          covering formulation technology or delivery devices (other than any Conjugate Technology comprised in IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>) <font style="font-size: 10pt; font-family: 'Times
            New Roman'; font-style: italic;"><u>unless</u></font> such Know-How is included in any Ionis Collaboration Know-How or Jointly-Owned Collaboration Know-How.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Licensed Patents</font>&#8221; means the Ionis
          Product-Specific Patents, Ionis Core Technology Patents, Ionis Manufacturing and Analytical Patents, Ionis Collaboration Patents, and Ionis&#8217; interest in any Jointly-Owned Collaboration Patents. For clarity, Licensed Patents do not include any
          Patent Rights filed after the Effective Date claiming formulation technology or delivery devices (other than any Conjugate Technology comprised in IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub>) <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>unless</u></font> such Patent Rights are included in any Ionis Collaboration Patents or Jointly-Owned Collaboration Patents.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Licensed Intellectual Property</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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Losses</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
            font-style: italic;">MAA</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8221; means a marketing authorization application filed with the </font>EMA <font style="font-size: 10pt; font-family: 'Times New Roman';">after
            completion of </font>Clinical Studies <font style="font-size: 10pt; font-family: 'Times New Roman';">to obtain </font>Approval <font style="font-size: 10pt; font-family: 'Times New Roman';">for a </font>Product <font style="font-size:
            10pt; font-family: 'Times New Roman';">under the centralized European filing procedure or, if the centralized </font>EMA <font style="font-size: 10pt; font-family: 'Times New Roman';">filing procedure is not used, filed using the applicable
            procedures in any </font>European Union <font style="font-size: 10pt; font-family: 'Times New Roman';">country or other country in Europe.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">MAA Approval</font>&#8221; means the Approval <font style="font-size: 10pt; font-family: 'Times New Roman';">of an </font>MAA <font style="font-size: 10pt; font-family: 'Times New Roman';">by (i) the </font>EMA <font style="font-size: 10pt; font-family: 'Times New Roman';">for a </font>Product










          <font style="font-size: 10pt; font-family: 'Times New Roman';">in any country in the </font>EU, or (ii) a Regulatory Authority for a Product in a European country that is a Major Market.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
            font-style: italic;">Major Market</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8221; means any of the following countries: the United States, Japan, the </font>United Kingdom<font style="font-size: 10pt; font-family: 'Times
            New Roman';">, </font>Germany<font style="font-size: 10pt; font-family: 'Times New Roman';">, </font>France<font style="font-size: 10pt; font-family: 'Times New Roman';">, </font>Italy, Spain, Brazil, Russia, India and China<font style="font-size: 10pt; font-family: 'Times New Roman';">.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Manufacture</font>&#8221; or &#8220;<font style="font-size:
            10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Manufactured</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 non-clinical, clinical, or commercial purposes, of API, Finished Drug Product or a
          Product.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Milestone Event</font>&#8221; means a Post-Licensing
          Milestone Event or a Sales Milestone Event, as applicable.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Minimum Third Party Payments</font>&#8221; means [***].</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
            font-style: italic;">NDA</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8221;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font><font style="font-size: 10pt; font-family: 'Times
            New Roman';">means a </font>New Drug Application <font style="font-size: 10pt; font-family: 'Times New Roman';">filed with the </font>FDA <font style="font-size: 10pt; font-family: 'Times New Roman';">after completion of </font>Clinical
          Studies <font style="font-size: 10pt; font-family: 'Times New Roman';">to obtain </font>Approval <font style="font-size: 10pt; font-family: 'Times New Roman';">for a Product</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';">in










            the United States.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
            font-style: italic;">NDA Approval</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8221; means the </font>Approval <font style="font-size: 10pt; font-family: 'Times New Roman';">of an </font>NDA <font style="font-size: 10pt;
            font-family: 'Times New Roman';">by the </font>FDA <font style="font-size: 10pt; font-family: 'Times New Roman';">for a Product</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';">in the U.S.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman';
            font-style: italic;">Sales</font>&#8221; definition in lieu of those deductions that are not accounted for on a Product-by-Product basis (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>, 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.</font></div>
      <div><br>
      </div>
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        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">74</font></div>
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">New Third Party Licenses</font>&#8221; has the meaning
          set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.3.2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Non-Clinical Studies</font>&#8221; means <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">in vitro</font> and <font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Non-Rare Disease Indication</font>&#8221; means <font style="font-size: 10pt; font-family: 'Times New Roman';">an Indication that is not a Rare Disease Indication</font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Non-Transferring Party</font>&#8221; has the meaning set
          forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.4</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Deadline</font>&#8221; has the meaning set forth
          in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Period</font>&#8221; has the meaning set forth in
          <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Party</font>&#8221; or &#8220;<font style="font-size: 10pt;
            font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Parties</font>&#8221; means Roche and Ionis individually or collectively.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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).</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Permitted Licenses</font>&#8221; means (1) licenses
          granted by Ionis before or after the Effective Date to any Third Party under the Ionis Core Technology Patents, the Ionis Manufacturing and Analytical Patents, or the Ionis Manufacturing and Analytical Know-How (but not under the Ionis
          Product-Specific Patents) to (a) use oligonucleotides (or supply oligonucleotides to end users) solely to conduct non-clinical research, or (b) enable such Third Party to manufacture or formulate oligonucleotides, where Ionis 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 Permitted Licenses as of the
          Effective Date is set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font> attached hereto.</font></div>
      <div><br>
      </div>
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        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">75</font></div>
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Phase 2 GA Trial</font>&#8221; means the Phase 2 Trial
          of IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in GA commenced by Ionis and to be conducted in accordance with the Development Plan.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Phase 2 [***] Trial</font>&#8221; means the anticipated
          phase 2a trial of IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> in [***] to be conducted by Ionis in accordance with the Development Plan.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Phase 2b [***] Trial</font>&#8221; has the meaning set
          forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Phase 2 Trial</font>&#8221; means a human clinical study
          of a Product 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Phase 2 Trial Data Package</font>&#8221; means, with
          respect to the Phase 2 GA Trial and the Phase 2 [***] Trial, the listing and tables of safety and efficacy data available to Ionis after the last patient has received his/her last dose of a Product in each such trial.&#160; If, as of the time the
          Phase 2 Trial Data Package is complete, there is available to Ionis additional Phase 2 Trial data or any additional earlier stage Clinical Study data for the Product pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section










              3.1.3</u></font>, then Ionis will provide such additional data to Roche along with the Phase 2 Trial Data Package.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 for a Product, 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 for such Product.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Post-Licensing Milestone Event</font>&#8221; has the
          meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.4</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Post-Licensing Milestone Payment</font>&#8221; has the
          meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.4</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Option Development Milestone Event</font>&#8221; has
          the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Option Development Milestone Payment</font>&#8221;
          has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.2</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Prior Agreement</font>&#8221; means the agreement listed
          on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 11.2.6</u></font> attached hereto.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Proceeding</font>&#8221; means an action, suit or
          proceeding.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Product</font>&#8221; means any product, including any
          combination product, containing IONIS-FB-L<sub style="vertical-align: bottom; line-height: 1; font-size: smaller;">Rx</sub> as an active pharmaceutical ingredient regardless of its finished form, formulation or dosage.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Product-Specific Patents</font>&#8221; means, with
          respect to a Product, Patent Rights Controlled by a Party or any of its Affiliates on or after the Effective Date claiming (i) the specific composition of matter of such Product, or (ii) methods of using such Product as a prophylactic or
          therapeutic, in each case to the extent necessary to Develop, Manufacture or Commercialize a Product; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided however</font>, Patent Rights Controlled by Ionis
          or any of its Affiliates that (a) include claims that are directed to subject matter applicable to ASOs or products in general, or (b) include an ASO, the sequence of which targets the RNA that encodes Factor B and ASOs that do not target the RNA
          encoding Factor B, will not be considered Product-Specific Patents, and in the case of (a) and (b), such Patent Rights will be considered Ionis Core Technology Patents.</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">76</font></div>
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Proposed Phase 2 Trials</font>&#8221; means the Phase 2
          GA Trial and the Phase 2 [***] Trial.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Prosecution and Maintenance</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Prosecution and Maintenance</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New
            Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
            font-style: italic;">Rare Disease Indication</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8221; means an Indication for which the expected U.S. patient population with a disease eligible for treatment by the Product is two
            hundred thousand (200,000) or less</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';">as determined by the FDA Office of Orphan Products Development.</font></font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
            font-style: italic;">Receiving Party</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 14.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Reduced Royalty Period</font>&#8221; has the meaning set
          forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2(d)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">[***]</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2(b)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Regulatory Authority</font>&#8221; means any
          governmental authority, including the FDA, EMA or Koseisho (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Regulatory Materials</font>&#8221; means regulatory
          applications, submissions, notifications, communications, correspondence, registrations, Approvals and/or other filings made to, received from or otherwise conducted with a Regulatory Authority that are necessary in order to Develop, Manufacture,
          obtain marketing authorization, market, sell or otherwise Commercialize a Product in a particular country or regulatory jurisdiction. Regulatory Materials include INDs, NDAs, MAAs, JNDAs, drug master files, presentations, responses, and
          applications for other Approvals. For clarity, Regulatory Materials also include written minutes of any meeting with any Regulatory Authorities, including minutes prepared by said Regulatory Authorities and those prepared by a Party&#8217;s personnel.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche</font>&#8221; has the meaning set forth in the
          Preamble of this Agreement.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche Basel</font>&#8221; has the meaning set forth in
          the Preamble of this Agreement.</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">77</font></div>
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 the Development Plan or the IDCP, that is necessary or useful to Develop,
          Manufacture or Commercialize a Product in the Field.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 the Development Plan or the IDCP, that are necessary or useful to Develop,
          Manufacture or Commercialize a Product in the Field.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche Collaboration Intellectual Property</font>&#8221;
          means Roche Collaboration Know-How, Roche Collaboration Patents and Roche&#8217;s interest in any Jointly-Owned Collaboration Intellectual Property.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche Full Royalty</font>&#8221; has the meaning set
          forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 the Development 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche US</font>&#8221; has the meaning set forth in the
          Preamble of this Agreement.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 the Development Plan or IDCP, (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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche-Prosecuted Patents</font>&#8221; has the meaning
          set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4(b)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche Reduced Royalty</font>&#8221; has the meaning set
          forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2(b)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche Supported Pass-Through Costs</font>&#8221; means
          [***].</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Roche Intellectual Property</font>&#8221; means Roche&#8217;s
          interest in Roche Collaboration Intellectual Property, Roche Know-How, Roche Patents and any trademarks described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.7</u></font>, owned, used, developed by, or
          licensed to Roche or its Affiliates that is necessary or useful to Develop, Manufacture or Commercialize a Product.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">[***]</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.7.2(b)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Sales</font>&#8221; of a Product in a particular period
          will mean the sum of (i) and (ii):</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">(i) 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, 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 style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"> <br>
        </font></div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">78</font></div>
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">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:</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4f5ff83bab65463193d3e1b2b1758eb8">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>, price capitation);</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div>
        <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z532b040f811f4bc997814b0a8681614f" 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;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">(b)</font></div>
              </td>
              <td style="vertical-align: top; width: auto;">
                <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">governmental price reductions and government mandated rebates;</font></div>
              </td>
            </tr>

        </table>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4bdd9dd44c074c849a400a3c525d33ed">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">chargebacks, including those granted to wholesalers, buying groups and retailers;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3448a008a4e7423a85df1694db4ca6af">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">customer rebates, including cash sales incentives for prompt payment, cash and volume discounts; and</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8d2ede21d9d5418bb98fd5ec6978f1ad">

              <tr>
                <td style="width: 72pt;"><br>
                </td>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">(e)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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).</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For the purpose of clarity, sales by Roche 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Sales</font>&#8221; calculated under this item
          (i).</font></div>
      <div><br>
      </div>
      <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">(ii) 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><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Sales Milestone Event</font>&#8221; has the meaning set
          forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.5</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Sales Milestone Payment</font>&#8221; has the meaning
          set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.5</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Second Indication</font>&#8221; means either (i) any
          second Indication if the applicable Post-Licensing Milestone Event has already been achieved by a Non-Rare Disease Indication, or (ii) the first Rare Disease Indication for which the applicable Post-Licensing Milestone Event is achieved.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Commercially Reasonable Efforts</font>&#8221;.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Step-In Party</font>&#8221; has the meaning set forth in
          <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.1</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 Intellectual Property or Roche Intellectual Property, as the case may be, licensed to such Party in accordance with the terms of this Agreement.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Third Party</font>&#8221; means a Person or entity other
          than the Parties or their respective Affiliates.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 Ionis and a Third Party (including any Additional Ionis In-License Agreements) that relate to a Product, Factor B, including field
          or territory restrictions, covenants, milestone payments, diligence obligations, sublicense revenue, royalties, or other payments.</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">79</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
        </font></div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Transferring Party</font>&#8221; has the meaning set
          forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 15.4</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Transition Activities</font>&#8221; has the meaning set
          forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 13.4.2(</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>i</u></font><font style="font-size: 10pt; font-family:
            'Times New Roman';"><u>)(i)</u></font>.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">United States</font>&#8221; or &#8220;<font style="font-size:
            10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">80</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Appendix 2</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Development and Commercialization Activities and</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Specific Performance Milestone Events</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">81</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Appendix 3</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Permitted Licenses as of the Effective Date</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">82</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
          <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Schedule 4.2</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Alliance Management Activities</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Each Alliance Manager is responsible for:</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z72063935edff4899a595936e1b851659">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Promoting the overall health of the relationship between the Parties;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z515fffa948fb442ba3999c0d5977ba8d">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 Development Plans;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf67a972f5b0c4a12964c3b41fe42576f">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Organizing JSC and JDC meetings, including agendas, drafting minutes, and publishing final minutes;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd3ebc1e6dd6a4e92b469ac668a0682c0">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Supporting the co-chairs of the JSC and JDC with organization of meetings, information exchange, meeting minutes, and facilitating dispute resolution as necessary;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z52bd8be4085c4b45ba6faaccbb3882ec">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Preparing status and progress reports on the above as determined necessary by the JSC and JDC;</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf118bd3b6c8a46e88956f337a2129ff6">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ensuring compliance in maintaining the Ionis Internal ASO Safety Database as outlined in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                          8.2.2(a)</u></font>; and</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="text-align: justify;">
        <div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z827ed2b845394a6b952b62614b85ef20">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(g)</font></td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ensuring proper approval of publications prior to submission as required in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 14.4</u></font>.</font></div>
                </td>
              </tr>

          </table>
        </div>
      </div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">83</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Schedule 4.4.2</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Ionis&#8217; Fully Absorbed Cost of Goods Methodology</font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Cost Estimate of API Cost per Kilogram</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">84</font></div>
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>9.7.2(e)</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Royalty Calculation Examples</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">85</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u> Schedule </u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>9.7.2(f)</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Allocation of Net Sales</font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">86</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 11.2.4(a)</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Ionis Core Technology Patents</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">87</font></div>
        <div style="page-break-after:always;" id="DSPFPageBreak">
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> 11.2.4(b)</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Ionis Manufacturing and Analytical Patents</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
        <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">88</font></div>
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size:
            10pt; font-family: 'Times New Roman';"><u> 11.2.4(c)</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Ionis Product-Specific Patents</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
      <div><br>
      </div>
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      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>11.2.6</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Prior Agreement</font></div>
      <div><br>
      </div>
      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
      <div><br>
      </div>
      <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
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      </div>
      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps;">Confidential</div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u> <br>
            </u></font></font></div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> 13.4.2(i)</u></font></font></div>
      <div><br>
      </div>
      <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Transition Activities</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Roche will perform Transition Activities, to the extent applicable at the time of the applicable termination, that are necessary to (1) provide patients
          with continued access to the applicable Products, (2) enable Ionis (or Ionis&#8217; designee) to assume and execute the responsibilities under all Approvals and then-ongoing Clinical Studies for the applicable Product, and (3) ensure long-term
          continuity of supply for the Product.&#160; Roche will perform the Transition Activities for Ionis through an agreed-upon schedule as set forth in an agreed upon transition plan, including but not limited in the following areas:</font></div>
      <div><br>
      </div>
      <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
      <div><br>
      </div>
      <div><br>
      </div>
      <div></div>
      <div>
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<DOCUMENT>
<TYPE>EX-10.68
<SEQUENCE>3
<FILENAME>exhibit10_68.htm
<DESCRIPTION>EXHIBIT 10.68
<TEXT>
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          <div style="text-align: right; font-family: &quot;Times New Roman&quot;; font-size: 10pt; font-variant: small-caps; font-weight: bold;">Execution Copy</div>
          <br>
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            <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">Exhibit 10.68</font></div>
            <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"> <br>
              </font></div>
            <div> Second Amended and Restated</div>
          </div>
        </div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;">Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement</font></div>
        <div><br>
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        <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;">Between</font></div>
        <div><br>
        </div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;">Ionis Pharmaceuticals, Inc.</font></div>
        <div><br>
        </div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;">And</font></div>
        <div><br>
        </div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;">Biogen MA Inc.</font></div>
        <div><br>
        </div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Dated October 17, 2018</font></div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
          </font></div>
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        <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Table of Contents</u></font></font></div>
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        <table cellspacing="0" cellpadding="0" border="0" id="zaadb8e5ece924bf0b157c12b97841886" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;">

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              <td style="vertical-align: top;" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top;" rowspan="1">
                <div style="text-align: right; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Page</u></font></font></div>
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            </tr>
            <tr>
              <td style="vertical-align: top;" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top;" rowspan="1">&#160;</td>
            </tr>
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                <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">ARTICLE 1. RESEARCH AND DEVELOPMENT</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">2</font></div>
              </td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Collaboration Overview</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">2</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Research Programs</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">3</font></div>
              </td>
            </tr>
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              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Process for Designating High Interest Targets as
                      Collaboration Targets or Biogen Alternate Modality Targets</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">8</font></div>
              </td>
            </tr>
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              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.4.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Process for Designating Ionis Neurology Targets as
                      Collaboration Targets</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">9</font></div>
              </td>
            </tr>
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              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.5.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Process for Designating ALS Targets as Collaboration Targets</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">9</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.6.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Consequences of Designating Collaboration Targets</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">10</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.7.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Consequences of Designating Biogen Alternate Modality Targets</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">11</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.8.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Deferring the Selection of a Collaboration Target or Biogen
                      Alternate Modality Target</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">11</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.9.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">End of Research Term</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">13</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.10.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis&#8217; Research and Development Responsibilities</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;">14</div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.11.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Resource Allocations</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">27</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.12.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Research and Development Costs Paid by Ionis</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">28</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.13.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Research and Development Costs Paid by Biogen</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">28</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.14.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Payment Mechanisms</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">29</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.15.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Participation in Regulatory Meetings</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">31</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.16.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Participation in Meetings Sponsored by a Party&#8217;s Clinical
                      Development Group</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">32</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.17.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Impact of Accelerated Development Path</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">32</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.18.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Research and Development Management</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">33</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 2. EXCLUSIVITY COVENANTS</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">40</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">2.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Exclusivity; Right of First Negotiation</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">40</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">2.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Right of First Negotiation for Follow-On Compounds</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">44</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 3. EXCLUSIVE OPTION</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">46</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">3.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Option</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">46</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">3.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Changing or Adding Modalities</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">48</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">3.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Restrictions on Ionis&#8217; Right to Grant Diagnostic Rights;
                      Right to Negotiate Diagnostic Rights</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">52</td>
            </tr>

        </table>
        <div><br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">i</font></div>
          <div style="page-break-after: always;" id="DSPFPageBreak">
            <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
        </div>
        <table cellspacing="0" cellpadding="0" border="0" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="ze5154ff4dbca40d1896059484ea054d7">

            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 4. LICENSE GRANTS</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">52</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">4.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">License Grants to Biogen</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">52</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">4.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Assignment of Ionis Product-Specific Patents; Grant Back to
                      Ionis</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">56</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">4.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Enabling Licenses</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">56</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">4.4.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Licenses to Ionis for Biogen Results</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">60</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">4.5.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Right to Obtain Direct License from Biogen to Ionis Partner;
                      Sublicensees of Ionis</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">61</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">4.6.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Ownership of and Assistance with Regulatory Filings</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">61</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">4.7.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Subcontracting</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">62</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">4.8.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Technology Transfer</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">63</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 5. DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">66</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">5.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen Diligence</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">66</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">5.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Regulatory Matters; Global Safety Database; Pharmacovigilance
                      Agreement</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">69</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">5.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Research and Manufacturing Records</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">73</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">5.4.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Product Development Plans for ALS Collaboration Programs and
                      Biogen Conducted Non-ALS Collaboration Programs</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">73</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 6. FINANCIAL PROVISIONS</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">73</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Up-Front Fee</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">73</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Drug Discovery Milestone Payments</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">73</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Milestone Payments for Achievement of Milestone Events by
                      Biogen Alternate Modality Products</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">74</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.4.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Non-ALS Collaboration Program Milestone Payments for
                      Achievement of Pre-Licensing Milestone Events</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">74</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.5.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">ALS Collaboration Program Milestone Payments for Achievement
                      of Pre-Licensing Milestone Events</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">75</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.6.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">License Fee</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">76</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.7.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Milestone Payments for Achievement of Post-Licensing
                      Milestone Events</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">76</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.8.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Limitations on Milestone Payments; Exceptions; Notice</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">77</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.9.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Royalty Payments to Ionis for Biogen Alternate Modality
                      Products</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">78</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.10.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Royalty Payments to Ionis for Collaboration Products</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">79</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.11.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Limitation on Aggregate Reduction for Royalties for
                      Collaboration Products</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">82</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.12.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Reverse Royalty Payments to Biogen for a Discontinued
                      Collaboration Product</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">82</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.13.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Third Party Payment Obligations</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">83</font></div>
              </td>
            </tr>

        </table>
        <div><br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">ii</font></div>
          <div style="page-break-after: always;" id="DSPFPageBreak">
            <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
        </div>
        <table cellspacing="0" cellpadding="0" border="0" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="za60c8a52aa1f4790be242a1f4c552db8">

            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.14.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Payments</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">84</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.15.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Audits</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">86</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.16.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Taxes</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">86</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">6.17.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Interest</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">88</font></div>
              </td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 7. INTELLECTUAL PROPERTY</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">88</font></div>
              </td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Ownership</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">88</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Prosecution and Maintenance of Patents</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">92</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Patent Costs</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">97</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.4.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Defense of Claims Brought by Third Parties</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">98</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.5.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Enforcement of Patents Against Competitive Infringement</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">100</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.6.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Other Infringement</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">103</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.7.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Patent Listing</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">103</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.8.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Joint Research Agreement under the Leahy-Smith America
                      Invents Act</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">104</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.9.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Obligations to Third Parties</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">104</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.10.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Additional Right and Exceptions</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">104</font></div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">7.11.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Patent Term Extension</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">105</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 8. REPRESENTATIONS AND WARRANTIES</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">105</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">8.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Representations and Warranties of Both Parties</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">105</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">8.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Representations and Warranties of Ionis</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">106</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">8.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis Covenants</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">108</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">8.4.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">DISCLAIMER</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: right;">109</div>
              </td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 9. INDEMNIFICATION; INSURANCE</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">109</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">9.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Indemnification by Biogen</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">109</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">9.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Indemnification by Ionis</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">110</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">9.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Procedure</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">110</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">9.4.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Insurance</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">111</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">9.5.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">LIMITATION OF CONSEQUENTIAL DAMAGES</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">111</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 10. TERM; TERMINATION</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">112</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">10.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Agreement Term; Expiration</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">112</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">10.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Termination of the Agreement</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">113</td>
            </tr>

        </table>
        <div><br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">iii</font></div>
          <div style="page-break-after: always;" id="DSPFPageBreak">
            <hr noshade="noshade" style="border-width: 0px; clear: both; margin: 4px 0px; width: 100%; height: 2px; color: #000000; background-color: #000000;"></div>
        </div>
        <table cellspacing="0" cellpadding="0" border="0" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="zc176aca7e46142c098252b137e85540c">

            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">10.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Alternative Remedies to Termination Available to Biogen Prior
                      to License Effective Date</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">117</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">10.4.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Consequences of Expiration or Termination of the Agreement</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">119</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 11. CONFIDENTIALITY</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">132</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">11.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Confidentiality; Exceptions</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">132</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">11.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Prior Confidentiality Agreement Superseded</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">132</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">11.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Authorized Disclosure</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">132</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">11.4.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Press Release; Publications; Disclosure of Agreement</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">133</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(204, 238, 255);" colspan="3" rowspan="1">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ARTICLE 12. MISCELLANEOUS</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">138</td>
            </tr>
            <tr>
              <td style="vertical-align: top; background-color: rgb(255, 255, 255);" colspan="3" rowspan="1">&#160;</td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;" rowspan="1">&#160;</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.1.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Dispute Resolution</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">138</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.2.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Governing Law; Jurisdiction; Venue; Service of Process</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">139</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.3.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Remedies</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">140</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.4.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Assignment and Successors</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">141</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.5.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Change of Control</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">141</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.6.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Protective Provisions</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">146</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.7.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Force Majeure</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">146</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.8.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Notices</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">147</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.9.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Export Clause</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">148</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.10.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Waiver</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">148</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.11.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Severability</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">148</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.12.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Entire Agreement</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">148</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.13.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Independent Contractors</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">149</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.14.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Interpretation</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">149</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.15.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Books and Records</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">149</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.16.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Further Actions</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;">149</div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.17.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Construction of Agreement</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">149</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.18.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Supremacy</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: right;">150</div>
              </td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(204, 238, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.19.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(204, 238, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Counterparts</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(204, 238, 255); text-align: right;">150</td>
            </tr>
            <tr>
              <td style="width: 5%; vertical-align: top; background-color: rgb(255, 255, 255);" colspan="1">&#160;</td>
              <td style="width: 6%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">12.20.</font></font></div>
              </td>
              <td style="width: 79%; vertical-align: top; background-color: rgb(255, 255, 255);">
                <div style="text-align: left; margin-right: 43.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Compliance with Laws</font></font></div>
              </td>
              <td style="width: 10%; vertical-align: top; background-color: rgb(255, 255, 255); text-align: right;">150</td>
            </tr>

        </table>
        <div> <br>
        </div>
        <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: 'Times New Roman'; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">iv</font></div>
          <div style="page-break-after: always;" id="DSPFPageBreak">
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        </div>
        <!--PROfilePageNumberReset%Num%1%%%-->
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">SECOND AMENDED AND RESTATED STRATEGIC NEUROLOGY DRUG DISCOVERY AND DEVELOPMENT COLLABORATION, OPTION AND LICENSE AGREEMENT</font></div>
        <div><br>
        </div>
        <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">This SECOND AMENDED AND RESTATED STRATEGIC NEUROLOGY DRUG DISCOVERY AND DEVELOPMENT COLLABORATION, OPTION AND LICENSE AGREEMENT (the
            &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Agreement</font>&#8221;) is entered into as of the 17th day of October, 2018 (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
              font-weight: bold; font-style: italic;">Second Amendment Date</font>&#8221;) by and between <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">Ionis Pharmaceuticals, Inc.</font>, a Delaware
            corporation, having its principal place of business at 2855 Gazelle Court, Carlsbad, CA 92010 (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis</font>&#8221;), and<font style="font-size:
              10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"> Biogen MA Inc.</font>, a Massachusetts corporation, having its principal place of business at 225 Binney Street, Cambridge, MA 02142 (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen</font>&#8221;). Biogen and Ionis each may be referred to herein individually as a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
              font-weight: bold; font-style: italic;">Party</font>&#8221; or collectively as the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Parties</font>.&#8221; Capitalized terms used in this Agreement,
            whether used in the singular or the plural, have the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 1</u></font>. All attached appendices and schedules are a part of
            this Agreement.</font></div>
        <div><br>
        </div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">RECITALS</font></div>
        <div><br>
        </div>
        <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">WHEREAS</font>, Ionis possesses certain Patent
            Rights, Know-How, technology and expertise with respect to antisense therapeutics, and has novel and valuable capabilities for the research, discovery, identification, synthesis and development of antisense therapeutics;</font></div>
        <div><br>
        </div>
        <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">WHEREAS</font>, Biogen has expertise in developing
            and commercializing human therapeutics, and is interested in entering into a strategic relationship with Ionis to explore potential targets for the treatment of neurological and neuromuscular diseases and to create antisense and other drugs to
            such targets;</font></div>
        <div><br>
        </div>
        <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">WHEREAS</font>, Biogen and Ionis now desire to
            enter into a new strategic collaboration in neurological and neuromuscular diseases to include (i) a neurological disease research program focused on the identification, validation, and applications of novel targets, (ii) a broad core
            technology research program focused on enhancing the Parties&#8217; knowledge of antisense oligonucleotide pharmacokinetics and pharmacodynamics in the central and peripheral nervous systems, (iii) a targeted drug discovery and development effort,
            and (iv) the exclusive opportunity for Biogen to select collaboration targets from among all available targets reaching target sanction status in Ionis&#8217; neurology program;</font></div>
        <div><br>
        </div>
        <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">WHEREAS</font>, with regard to certain neurology
            targets Biogen selects as collaboration targets for development using an antisense molecule, Biogen desires Ionis to (i) identify a development candidate for each of the collaboration targets, (ii) develop the development candidate through
            completion of the first clinical trial designed to demonstrate proof of mechanism or proof of therapeutic benefit, and (iii) provide Biogen an option to obtain an exclusive license under this Agreement to develop, manufacture and commercialize
            collaboration products in the Field;</font></div>
        <div><br>
        </div>
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          <div id="DSPFPageBreak" style="page-break-after:always;">
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        <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">WHEREAS</font>, for certain neurology targets
            relating to ALS and certain other indications, the Parties will collaborate to develop and identify antisense and other drugs to such targets as provided herein;</font></div>
        <div><br>
        </div>
        <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">WHEREAS</font>, Biogen and Ionis entered into that
            certain Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement, as amended (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Original Agreement</font>&#8221;)











            dated September 5, 2013 (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Effective Date</font>&#8221;) and subsequently entered into an Amended and Restated Strategic Neurology Drug Discovery
            and Development Collaboration, Option and License Agreement (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">First Amended and Restated Agreement</font>&#8221;) dated October 20, 2017 (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">First Amendment Date</font>&#8221;); and</font></div>
        <div><br>
        </div>
        <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">WHEREAS</font>, Biogen and Ionis seek to amend and
            restate the First Amended and Restated Agreement in its entirety as set forth herein;</font></div>
        <div><br>
        </div>
        <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">NOW, THEREFORE</font>, in consideration of the
            respective covenants, representations, warranties and agreements set forth herein, the Parties hereto agree as follows:</font></div>
        <div><br>
        </div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 1.</font></div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">RESEARCH AND DEVELOPMENT</font></div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="ze50ba6cd3a64479ba3ad90fb64c2116c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Collaboration Overview</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z4bee9553ce514e979267f166139b976d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.1.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The intent of the Collaboration is for the Parties to conduct (i) a neurological disease research program focused on the identification, validation, and applications of
                        novel Neurology Targets, (ii) a broad core technology research program focused on enhancing the Parties&#8217; knowledge of ASO pharmacokinetics and pharmacodynamics in the central and peripheral nervous systems, and (iii) an expanded
                        drug discovery and development effort in Neurological Disease, including a program specifically focused on certain ALS Targets. This Agreement also provides Biogen the exclusive opportunity to select Collaboration Targets and Biogen
                        Alternate Modality Targets from among all available Neurology Targets Ionis is independently researching up through Target Sanction.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z811ac830f79840ad985441764678e009" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.1.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Once a Neurology Target reaches Target Sanction, the Neurology Target may be selected as a Collaboration Target, a Biogen Alternate Modality Target or both under this
                        Agreement. Ionis will generate at least one Development Candidate, if feasible for each Collaboration Program that is not focused on an ALS Target or a Biogen Conducted Non-ALS Target; and advance each such Development Candidate
                        through the completion of the first PoC Trial under the applicable Collaboration Program.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">2</font></div>
          <div id="DSPFPageBreak" style="page-break-after:always;">
            <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z9bacd9ff848840a6a24db28e8a62c535" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.1.3.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">When an ALS Target is selected as a Collaboration Target, Ionis will generate at least one Development Candidate, if feasible, for each ALS Collaboration Program; and
                        Biogen will use Commercially Reasonable Efforts to advance each such Development Candidate through at least the completion of the first PoC Trial under the applicable Collaboration Program.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z6e09514dbd52420b8ae4cf87ec92a124" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.1.4.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Once a Biogen Conducted Non-ALS Target reaches Target Sanction, the Biogen Conducted Non-ALS Target may be selected as a Collaboration Target under this Agreement.
                        Ionis will generate at least one Development Candidate, if feasible for each Biogen Conducted Non-ALS Collaboration Program; and Biogen will use Commercially Reasonable Efforts to advance each such Development Candidate through at
                        least the completion of the first PoC Trial under the applicable Collaboration Program.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zea1d99b0ebaa44f1aa834ba60b8c1e3d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.1.5.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will provide Biogen an option to further Develop and ultimately Commercialize (a) Compounds and Collaboration Products under such Collaboration Programs, (b)
                        Biogen Alternate Modality Products or (c) both Collaboration Products and Biogen Alternate Modality Products, in each case, under an exclusive license from Ionis.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z36086f48af3c4af3921244eaaafa4949" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.1.6.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Parties have agreed to form a collaboration steering committee to oversee the Collaboration under this Agreement, a joint research committee reporting to the CSC to
                        oversee the Core Research Program [***], the Neurological Disease Research Program, and each ASO Development Candidate Identification Plan, and one or more joint development committees reporting to the CSC to oversee the development
                        activities for Development Candidates.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zec5801bbd5514bbfa76dc22c46f01f38" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.1.7.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The purpose of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.1</u></font> is to provide a high-level overview of the roles,
                        responsibilities, rights and obligations of each Party under this Agreement, and therefore this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.1</u></font> is qualified in its entirety by the more
                        detailed provisions of this Agreement set forth below.</font></div>
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            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zee54d504760d45d6928057c5d40fa4d2" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Research Programs</u></font>. Subject to and in accordance with the terms of this
                        Agreement, during the Research Term, Ionis and Biogen will conduct two research programs, each under a separate mutually agreed plan. The first research program will cover research focused on enhancing the Parties&#8217; knowledge of ASO
                        pharmacokinetics and pharmacodynamics in the central and peripheral nervous systems (such program, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Core Research Program</font>&#8221;
                        and the plan for such program, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Core Research Plan</font>&#8221;). The second research program will focus on the identification and
                        validation of High Interest Targets, and the identification of ALS Targets, that are eligible to become Collaboration Targets (such program, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                          font-style: italic;">Neurological Disease Research Program</font>&#8221; and the plan for such program, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurological Disease
                          Research Plan</font>&#8221;).&#160; Drafts of the Core Research Plan and the initial Neurological Disease Research Plan have been mutually agreed upon by the Parties in writing on or prior to the Effective Date<font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-variant: small-caps;">. </font>The Parties will finalize these initially agreed draft plans within [***] days after the Effective Date. Thereafter, the Parties will update such plans at least
                        once before the beginning of each Calendar Year, and submit them to the Neurology JRC for its review and approval.&#160; Each update to the Neurological Disease Research Plan will include, at a minimum (a) the activities to support
                        Target Sanction in the Calendar Year covered by such Neurological Disease Research Plan, (b) any Neurological Disease research to support Collaboration Programs, and (c) any ongoing work on High Interest Targets from prior Calendar
                        Years.&#160; Notwithstanding the foregoing, neither Party will be required to complete any activities under the Core Research Plan or Neurological Disease Research Plan if such Party in good faith believes that such activities are not
                        technically feasible given the then-current state of the art.</font></div>
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            </table>
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        <div><br>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">3</font></div>
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            <table cellspacing="0" cellpadding="0" id="zb59856f96810463e9949ad574d89c54f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.2.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Research Term</u></font>.<font style="font-size: 10pt; font-family: 'Times New
                          Roman'; font-weight: bold;">&#160;</font>The term for the conduct of the Core Research Program and the Neurological Disease Research Program will begin on the Effective Date and will end on the sixth anniversary of the Effective Date,
                        unless either of such programs is terminated earlier by the Parties by written agreement (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Research Term</font>&#8221;); <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that with respect to the Neurological Disease Research Program, (a) Ionis will not be required to begin target validation
                        activities under the Neurological Disease Research Program (i) after the [***] anniversary of the Effective Date for any target that is not an ALS Target or (ii) after the [***] anniversary of the Effective Date for any ALS Target,
                        in each case, unless otherwise agreed to by the Parties, and (b) if any target validation activities that are Ionis Activities are ongoing under the Neurological Disease Research Plan on such sixth anniversary, then Ionis will
                        complete such activities in accordance with the Neurological Disease Research Plan, and the Research Term will be extended until the completion thereof.</font></div>
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            </table>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z6ed565b7489841cdba75dae6b04fe207" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.2.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Core Research Program</u></font>. The Core Research Program activities will focus
                        primarily on investigating and optimizing delivery of ASOs to the CNS. Ionis will use Commercially Reasonable Efforts to conduct the Ionis Activities under the Core Research Program, and Biogen will use Commercially Reasonable
                        Efforts to conduct the Biogen Activities under the Core Research Program. The Neurology JRC will update the Core Research Plan as needed during the Research Term.&#160; As of the Second Amendment Date the Parties have completed all
                        activities under the Core Research Program.</font></div>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <div>
              <div>
                <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z0ea8ed05a2474c1b9d652caa44165a88" 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><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.2.3.</font></div>
                      </td>
                      <td style="align: left; vertical-align: top; width: auto;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Neurological Disease Research Program</u></font>. The Neurological Disease
                            Research Program activities will focus primarily on identifying and validating novel Neurology Targets and prioritizing a list of High Interest Targets (defined below), including ALS Targets.</font></div>
                      </td>
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                </table>
              </div>
            </div>
          </div>
        </div>
        <div><br>
        </div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">4</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="z0db86152e140469eb036e3747b3aba5b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>High Interest Targets</u></font>. Under the Neurological
                        Disease Research Plan, Biogen will establish a prioritized list of Neurology Targets, including ALS Targets to designate as high interest targets (each such target, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
                          font-weight: bold; font-style: italic;">High Interest Target</font>&#8221; and such list the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">High Interest Target List</font>&#8221;).&#160; The
                        number of High Interest Targets cannot exceed [***].&#160; The initial High Interest Target List has been mutually agreed upon by the Parties in writing on or prior to the Effective Date.&#160; Biogen will present updates, if any, to the High
                        Interest Target List at each meeting of the Neurology JRC. Each Neurology Target added to the High Interest Target List will be a High Interest Target; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style:
                          italic;">provided, however</font>,<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#160;</font>that if Ionis notifies Biogen within [***] days after the date on which Ionis receives a High Interest
                        Target List containing a new High Interest Target that (i) [***], (ii) such gene target is not eligible to become a High Interest Target hereunder [***], or (iii) such gene target is [***], then the applicable gene target will not
                        be a High Interest Target hereunder. When Biogen adds a Neurology Target to the High Interest Target List, Biogen will identify on the High Interest Target List if Biogen intends such target to be an ALS Target.&#160; Biogen may convert
                        an ALS Target into a High Interest Target that is not an ALS Target at any meeting of the Neurology JRC. For clarity, Biogen may add any Ionis Neurology Target to the High Interest Target List until such Ionis Neurology Target is
                        less than [***] months away from the date on which Ionis in good faith believes [***]. In addition, once target validating activities for a High Interest Target have been initiated under the Neurological Disease Research Plan or by
                        Ionis independently (as presented by Ionis to the Neurology JRC),<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#160;</font>Biogen may not remove a High Interest Target from the High Interest Target
                        List until [***]. The Parties acknowledge and agree that, as of August 4, 2014, [***] has been designated as a Collaboration Target that is an ALS Target under this Agreement. The Parties further acknowledge and agree that (1)
                        notwithstanding any scientific determination regarding [***], the ALS Collaboration Program for [***] shall be treated as an ALS Collaboration Program that is <font style="font-size: 10pt; font-family: 'Times New Roman';
                          font-style: italic;"><u>not</u></font> a [***] Collaboration Program for purposes of this Agreement, (2) [***] is not a Multi-Indication Target (as defined below) and (3) [***] is deemed to be a Pre-Existing Target (as defined
                        below) for purposes of this Agreement.</font></div>
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            </table>
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        <div><br>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">5</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="zea60f1b39c6246568959fc086c2e1ed5" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Multi-Indication Targets</u></font>.&#160; No later than [***] days
                        following the addition of a particular High Interest Target to the High Interest Target List, Ionis may notify Biogen in writing that Ionis believes, in good faith, based upon published scientific literature or the results of Ionis&#8217;
                        internal research efforts, that such High Interest Target may have therapeutic benefit beyond Neurological Disease (each such High Interest Target, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                          font-style: italic;">Multi-Indication Target</font>&#8221;, and each such notice a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Multi-Indication Target Notice</font>&#8221;). The
                        Multi-Indication Target Notice will (i) include materials supporting Ionis&#8217; belief that such High Interest Target may have therapeutic benefit beyond Neurological Disease and (ii) specify whether Ionis in good faith believes such
                        Multi-Indication Target is a Primarily Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other Multi-Indication Target. If within [***] days of its receipt of a Multi-Indication Target Notice Biogen notifies
                        Ionis in writing that Biogen wishes to remove the applicable Multi-Indication Target from the High Interest Target List, then such Multi-Indication Target will not be a High Interest Target but will continue to be a Neurology Target
                        unless and until its status changes by operation of this Agreement. If Biogen does not so notify Ionis that it wishes to remove the applicable Multi-Indication Target from the High Interest Target List within such [***] day period,
                        within [***] days after Biogen&#8217;s receipt of the applicable Multi-Indication Target Notice, Biogen will notify Ionis whether it agrees with Ionis&#8217; determination as to whether the applicable Multi-Indication Target is a Primarily
                        Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other Multi-Indication Target. If Biogen and Ionis agree with respect to such determination, then the agreed upon designation will be binding upon the Parties
                        with respect to such Multi-Indication Target and the provisions of clauses (b)-(e) of <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font> will apply with respect to such
                        Multi-Indication Target. If Biogen does not agree with such determination, the Multi-Indication Target will be designated as a Primarily Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other
                        Multi-Indication Target in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2.3(d)</u></font> upon the Neurology JRC agreeing to conduct target validating activities for such
                        Multi-Indication Target under the Neurological Disease Research Plan pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2.3(d)</u></font> and prior to the commencement of such activities. For
                        the avoidance of doubt, if Ionis fails to deliver a Multi-Indication Target Notice within [***] days after the addition of a particular High Interest Target to the High Interest Target List, such High Interest Target will not be a
                        Multi-Indication Target hereunder.</font></div>
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            </table>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z4a455b70ed4e4f25b7e18885109c0bf9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Target Validation Under the Neurological Disease Research
                            Program</u></font>.<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>The Neurology JRC will agree on an update to the Neurological Disease Research Plan annually. The first [***] years of
                        the Research Term are planned to focus on validating the role of novel Neurology Targets that are not ALS Targets in Neurological Disease, with the goal of achieving Target Sanction for High Interest Targets, and providing for all
                        pre-clinical development work under the Neurological Disease Research Plan required to validate such High Interest Targets. Biogen will have final decision-making authority with respect to [***]. The Neurology JRC will determine the
                        number of High Interest Targets for which activities to support Target Sanction will be conducted during each Calendar Year of the Research Term, which number will reflect the number of targets the Neurology JRC determines that
                        Ionis can, in the exercise of Commercially Reasonable Efforts, (i) [***], (ii) [***], (iii) [***], and taking into account resources that may be used for ALS Targets, in each case using the number of FTEs provided for under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.11</u></font>.&#160; Prior to the initiation of any activities to support Target Sanction with respect to any High Interest Target, Biogen will notify Ionis if such
                        High Interest Target is a Neurology Target with respect to which Biogen has [***] intended for a neurology indication (a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Existing







                          Target</font>&#8221;).&#160; Ionis will use Commercially Reasonable Efforts to conduct such activities to support Target Sanction on such High Interest Targets each year during the Research Term.&#160; The Neurological Disease Research Plan will
                        identify which Party will be responsible for the activities related to validation of such targets. It is anticipated that Biogen will perform the [***] required under the Neurological Disease Research Plan where Biogen, at such
                        time, already has in place at Biogen or through its collaborators the appropriate [***] and the ability to conduct such [***]; and that all other such [***] will be conducted by Ionis. Each Party will be responsible for the cost of
                        the work it conducts under the Neurological Disease Research Program as more specifically detailed in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.12</u></font> and<font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u> Section 1.13</u></font>.&#160; Neither Party will be required to conduct work using [***] that are not similar in cost or technical feasibility to the [***] such Party has obtained from Third
                        Parties and uses for its other programs.</font></div>
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        <div><br>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">6</font></div>
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            <table cellspacing="0" cellpadding="0" id="z879ae2f934134db6876a7bd7a60b8ab1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Target Validation for Multi-Indication Targets</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">. </font>If the Neurology JRC agrees to conduct target validating activities under the Neurological Disease Research Plan with respect to any
                        Multi-Indication Target that the Parties did not agree to designate as a Primarily Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other Multi-Indication Target pursuant to <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 1.2.3(b)</u></font>, within [***] days after such agreement, the CSC will meet to determine whether such target is a Primarily Neuro Multi-Indication Target, Equal Multi-Indication
                        Target or Primarily Other Multi-Indication Target. If the CSC agrees on the appropriate classification for such Multi-Indication Target, the provisions of clauses (b)-(e) of <font style="font-size: 10pt; font-family: 'Times New
                          Roman'; font-variant: small-caps;"><u>Appendix 3</u></font> will apply with respect to such Multi-Indication Target. If the CSC cannot unanimously agree on the appropriate classification for a Multi-Indication Target at the
                        applicable meeting, then such classification will be made pursuant to clause (a) of <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>.</font></div>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zb93b4ae844234430be6a5ee6367c02ca" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Neurology Targets that are not High Interest Targets</u></font>.
                        Subject to the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.4</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(b)</u></font> below, during
                        the Research Term, either Party may work outside of the Collaboration on any Neurology Target that is <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>not</u></font> (i) a High Interest Target for which target
                        validating activities are planned under the then-current Neurological Disease Research Plan, (ii) a Collaboration Target, or (iii) a Biogen Alternate Modality Target.</font></div>
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        <div><br>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">7</font></div>
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            <table cellspacing="0" cellpadding="0" id="zd298e56632a6442096f528e839a600ad" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.2.4.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Provision of ASOs for Research Outside of the Neurological
                            Disease Research Program</u></font>.<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>During the Research Term, in accordance with and subject to the terms and conditions set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;">&#160;</font>(which represent the
                        non-financial terms upon which Ionis generally provides its partners on a non-exclusive basis, research ASOs for independent research), Biogen may ask Ionis to use its ASO technology to provide research ASOs for up to [***] gene
                        targets each successive [***] month period that are the focus of Biogen programs that are not part of the Collaboration.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z9dd00f2f90af47cfac84c87ad680be44" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.3.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Process for Designating High Interest Targets as Collaboration Targets or Biogen
                            Alternate Modality Targets</u></font>.&#160;&#160; After the Parties complete the activities to achieve Target Sanction for a particular High Interest Target that is not an ALS Target, Ionis will deliver a Target Sanction Data Package for
                        such High Interest Target to the Neurology JRC for review as soon as reasonably practicable.&#160; Each time Ionis delivers the Neurology JRC a Target Sanction Data Package for a High Interest Target under this <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 1.3</u></font> the Parties will schedule a meeting of the Neurology JRC within [***] days following delivery of such Target Sanction Data Package. At such meetings the Neurology
                        JRC will determine and record in the Neurology JRC minutes whether an ASO or Alternate Modality is the best therapeutic approach to pursue for such High Interest Target.&#160; If the Neurology JRC cannot unanimously agree on which
                        modality is the best therapeutic approach to pursue for a particular High Interest Target at such meeting, Biogen will have final decision-making authority on the matter. Within the later of (a) [***] days following such meeting of
                        the Neurology JRC or (b) [***] days after Biogen&#8217;s receipt of the Target Sanction Data Package for such High Interest Target, by written notice to Ionis, Biogen will either designate such High Interest Target as a Collaboration
                        Target (in which case <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.6</u></font> will apply), a Biogen Alternate Modality Target (in which case <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 1.7</u></font> will apply), or a Deferred Target (in which case <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8</u></font> will apply). If Biogen does not designate such High
                        Interest Target as a Collaboration Target, a Biogen Alternate Modality Target, or Deferred Target within the timeframe set forth in the previous sentence, then (i) such High Interest Target (A) will not be designated a Collaboration
                        Target or Biogen Alternate Modality Target and (B) will no longer be a Neurology Target under this Agreement and (ii) the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(f)</u></font>
                        will apply with respect to such target.&#160; Notwithstanding the foregoing, if Ionis delivers the Neurology JRC a Target Sanction Data Package for a High Interest Target under this <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 1.3</u></font> and such High Interest Target is a Pre-Existing Target, then the Neurology JRC will not meet to discuss which modality is the best therapeutic approach for such High Interest Target, but Biogen
                        will have [***] days after receipt of such Target Sanction Data Package to designate such High Interest Target as a Collaboration Target or a Deferred Target (treating, for purposes of <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 1.8</u></font>, such target as a High Interest Target for which the best therapeutic modality was determined to be an ASO) by written notice to Ionis, but will not have the right to designate such
                        High Interest Target as a Biogen Alternate Modality Target.&#160; If Biogen does not designate such High Interest Target as a Collaboration Target or Deferred Target within the timeframe set forth in the previous sentence, then (1) such
                        High Interest Target (I) will not be designated a Collaboration Target or a Deferred Target and (II) will no longer be a Neurology Target under this Agreement and (2) the provisions of clause (A) (but not clause (B)) of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(f)</u></font> will apply with respect to such target.</font></div>
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        </div>
        <div><br>
        </div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">8</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="z874fe5454d2441c5a03fc56a5893205a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.4.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Process for Designating Ionis Neurology Targets as Collaboration Targets</u></font>.<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160; </font>If, during the Research Term through June 7, 2018 (except, solely in the case of [***] and [***], through the end of the Research Term) in the
                        course of conducting work outside of the Collaboration with respect to any Ionis Neurology Target, Ionis achieves Target Sanction with respect to such Ionis Neurology Target, then Ionis will deliver a Target Sanction Data Package
                        for such Ionis Neurology Target to the Neurology JRC for review as soon as reasonably practicable. Within [***] days after the date Ionis delivered the applicable Target Sanction Data Package to the Neurology JRC, by written notice
                        to Ionis, Biogen will either designate such Ionis Neurology Target as a Collaboration Target (in which case <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.6</u></font> will apply), or, to the extent
                        permitted below, a Biogen Alternate Modality Target (in which case <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.7</u></font> will apply). If such Ionis Neurology Target was not a High Interest Target
                        on the date of Target Sanction, Biogen will only have the right to designate such target as a Collaboration Target (and not, for the avoidance of doubt, as a Biogen Alternate Modality Target). If Biogen does not designate such Ionis
                        Neurology Target as a Collaboration Target, or a Biogen Alternate Modality Target within [***] days after the date Ionis delivered the applicable Target Sanction Data Package to the Neurology JRC, such Ionis Neurology Target will no
                        longer be a Neurology Target under this Agreement and Ionis and its Affiliates may work independently or with any Third Party with respect to the discovery, research, development, and commercialization of ASOs (or any other
                        compounds) targeting such Ionis Neurology Target.</font></div>
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            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z53ddf7907d304d8e8c9b9f2bfa4cecce" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.5.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Process for Designating ALS Targets as Collaboration Targets</u></font>. If Biogen
                        desires Ionis to initiate ASO drug discovery activities on a particular ALS Target, then at the same time the Neurological Disease Research Plan for the Calendar Year in which Biogen desires Ionis to initiate such activities is
                        updated to include activities for such Calendar Year, Biogen will designate such ALS Target as a Collaboration Target by providing written notice to Ionis; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style:
                          italic;">provided</font>, if such ALS Target is a Multi-Indication Target, Biogen cannot designate such ALS Target as a Collaboration Target until such target has been classified by the CSC or by operation of <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font> as a Primarily Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other Multi-Indication Target. In
                        addition, Biogen cannot designate more than [***] ALS Targets as Collaboration Targets in any successive [***]-month period, and the total number of ALS Targets that are Collaboration Targets cannot exceed [***] without the Parties&#8217;
                        mutual agreement.</font></div>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">9</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="zcff34fc85e404231b827d68b5eb356ba" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.6.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Consequences of Designating Collaboration Targets</u></font>.</font></div>
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        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z8e3e015a8d3d4edc8c195127835db0e2" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.6.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to and in accordance with the terms of this Agreement, for each Collaboration Target designated under <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 1.3,</u></font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.4,</u></font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.5</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.1</u></font> or <font style="font-size: 10pt; font-family: 'Times
                          New Roman';"><u>Section 3.2.4.1</u></font>, Ionis and Biogen will be responsible for conducting collaboration programs in accordance with this Agreement to discover, Develop and Manufacture Collaboration Products and, upon
                        Biogen&#8217;s exercise of the applicable Option, Biogen will be responsible for Commercializing Collaboration Products (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaboration








                          Program</font>&#8221;).&#160; For each Collaboration Target, an ASO Development Candidate Identification Plan and Initial Development Plan will be established pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                            1.10.1</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(d)</u></font>, respectively. For each Collaboration Program, Ionis will use its Commercially Reasonable Efforts to (i)
                        conduct drug discovery activities, according to the applicable ASO Development Candidate Identification Plan to identify a Development Candidate for the applicable Collaboration Target, and (ii) for each Collaboration Program that
                        is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, conduct drug development activities for each Development Candidate through completion of the first PoC Trial in accordance with the applicable
                        Initial Development Plan; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided </font>that, in each case unless the Neurology JRC unanimously agrees under <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 1.11</u></font> to re-allocate resources to support additional Collaboration Programs and, except for any activities Ionis conducts for Collaboration Targets designated under that
                        certain side letter between the Parties, dated as of October 28, 2016 (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">ALS Letter Agreement</font>&#8221;) attached hereto as <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 1.6.1</u></font>, Ionis will not be required to commence
                        work on more than [***] Collaboration Programs in any rolling [***] month period; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, further</font>,<font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-style: italic;">&#160;</font>that, if Biogen has designated more than [***] High Interest Targets as Collaboration Targets pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                            1.3</u></font> in any rolling [***] month period, such excess targets will be treated the same as &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Deferred Targets</font>&#8221; hereunder until the
                        earlier of (a) such time as Ionis has agreed to commence work on such excess targets, (b) such time as Ionis is otherwise obligated to commence such work hereunder because Ionis has commenced work on fewer than [***] targets in a
                        rolling [***] month period and (c) the expiration of the Research Term and, notwithstanding the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.1</u></font>, Biogen will not be obligated
                        to make the payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.1</u></font> with respect to such target until such time. For each ALS Collaboration Program and each Biogen Conducted Non-ALS
                        Collaboration Program, Biogen will use its Commercially Reasonable Efforts to conduct drug development activities for each Development Candidate through completion of the [***] in accordance with the applicable Initial Development
                        Plan.</font></div>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z0b9c2c62e3ce4c8ea660900b0a343bc3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.6.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Notwithstanding the foregoing, if the applicable Collaboration Target is an Equal Multi-Indication Target, the Parties will not conduct any activities under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.6</u></font> unless and until Ionis and Biogen have agreed on a development plan and enhanced economic provisions to be paid by Biogen for the Non-Neurological
                        Indications pursuant to clause (c) of <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>.</font></div>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">10</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="z1ab9c255551e402c85a4b1192dedf2dd" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.7.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Consequences of Designating Biogen Alternate Modality Targets</u></font>. If Biogen
                        designates a particular Neurology Target as a Biogen Alternate Modality Target under this Agreement (including <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.3</u></font>, <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 1.4</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                            3.2.2</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.4.2</u></font>), Biogen will pay Ionis the milestone payment under <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 6.2.2</u></font> within 45 days of the designation of such Biogen Alternate Modality Target, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, if
                        Biogen determines that an HSR Filing is required to be made under the HSR Act for Biogen to receive the license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> with respect to
                        such Biogen Alternate Modality Target and notifies Ionis of such determination within five days after the designation of such Biogen Alternate Modality Target, the Parties will promptly file an HSR Filing in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.4</u></font> and the due date for Biogen to pay Ionis the milestone payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                            6.2.2</u></font> will be extended until 5:00 pm (Eastern Time) on the [***] Business Day after the HSR Clearance Date.</font></div>
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            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="ze1ae79b7814c4be5886cabdca68a6a1a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.8.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Deferring the Selection of a Collaboration Target or Biogen Alternate Modality
                            Target</u></font>.</font></div>
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            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z1df173ed15e54da5927a4decb566d1c1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.8.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Right to Defer</u></font>. If under <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 1.3</u></font> Biogen provides Ionis a notice (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Deferral Notice</font>&#8221;)








                        electing to defer selecting a High Interest Target as a Collaboration Target or a Biogen Alternate Modality Target (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Deferred











                          Target</font>&#8221;), and there is at least [***] at the time of Deferral Notice, then Biogen may defer selecting such High Interest Target as a Collaboration Target or a Biogen Alternate Modality Target for a period of up to the
                        shorter of (i) (A) with respect to any High Interest Target for which the best therapeutic modality was determined to be an ASO, [***] or (B) with respect to any High Interest Target for which the best therapeutic modality was
                        determined to be an Alternate Modality, [***], or (ii) the end of the Research Term (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Deferral Period</font>&#8221;); <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, Biogen may only defer up to [***] High Interest Targets under this <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 1.8.1</u></font> at any given time. For the avoidance of doubt, the limitation in the preceding proviso will not apply with respect to any Collaboration Target that is treated the same as a Deferred Target
                        pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.6.1.</u></font></font></div>
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            </table>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z15655b9a3ea74547a23d48ce3ffa5585" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.8.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Deferral Fee</u></font>. For each High Interest Target Biogen
                        elects to defer under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8</u></font>, Biogen will pay Ionis an annual deferral fee of (a) $[***] for each such Deferred Target for which the best
                        therapeutic approach is determined to be an ASO or (b) $[***] for each such Deferred Target for which the best therapeutic approach is determined to be an Alternate Modality, in each case, in accordance with <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 1.3</u></font>. No deferral fee will be due under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.2</u></font> with respect to any Collaboration
                        Target that is treated the same as a Deferred Target pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.6.1</u></font>. Each annual deferral fee for a Deferred Target will be paid in advance for
                        the ensuing [***] month period, with the initial annual deferral fee for all Deferred Targets due within [***] days after the date Biogen delivers the applicable Deferral Notice to Ionis, and each annual deferral fee due thereafter
                        during the Deferral Period on the anniversary of the date Biogen delivered such Deferral Notice. If any such annual deferral fee is due after the date that is [***] prior to the expiration of the Research Term, such deferral fee
                        will be pro-rated to account for the number of days remaining in the Research Term (where such pro-ration will be based on the number of days between the due date for such deferral fee and the end of the Research Term, divided by
                        365).</font></div>
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        <div><br>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">11</font></div>
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            <table cellspacing="0" cellpadding="0" id="z5d45a08afda845bea29a798dc024d497" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.8.3.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Designating a Deferred Target as a Collaboration Target or
                            Biogen Alternate Modality Target; Credit for Deferral Fees</u></font>. Biogen may designate a Deferred Target as a Collaboration Target or Biogen Alternate Modality Target, as applicable, by delivering written notice to Ionis of
                        such designation (and if a Biogen Alternate Modality Target, the milestone payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.2)</u></font>, before the expiration of the applicable Deferral
                        Period under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8</u></font>; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Biogen
                        will not be permitted to designate such Deferred Target as a Biogen Alternate Modality Target if such Deferred Target is a Pre-Existing Target.&#160; Biogen may credit [***]% of the total amount paid to Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.2</u></font> for such Deferred Target against the milestone payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.1</u></font>
                        or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.2</u></font>, as applicable, for such Deferred Target. If Biogen does not designate a Deferred Target as a Collaboration Target or Biogen Alternate
                        Modality Target in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.3</u></font> before the expiration of the applicable Deferral Period, then such gene target will no longer be a
                        Neurology Target under this Agreement and any payments made by Biogen under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8</u></font> for such Deferred Target will be non-creditable and
                        non-refundable.</font></div>
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        <div><br>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z61265d70fe284602bb74d799a2c87313" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.8.4.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Accelerating the Deferral Period with a Deferred Target Development Candidate</u></font>.</font></div>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zb762591314fd4b7aa9604070b1b82c93" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis and its Affiliates may, for its own benefit and not for the benefit of any Third Party, conduct drug discovery activities to identify a Development Candidate for
                        any Deferred Target for which the best therapeutic modality was determined to be an ASO (such Development Candidate, a<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>&#8220;<font style="font-size:
                          10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Deferred Target Development Candidate</font>&#8221;); <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that
                        Ionis may not use the FTEs provided for under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.11</u></font> to conduct such activities. Ionis will notify the Neurology JRC of any such activities and keep
                        the Neurology JRC reasonably apprised of the status thereof at each meeting of the Neurology JRC. If Ionis designates a Deferred Target Development Candidate targeting a particular Deferred Target (such target, an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Accelerated Target</font>&#8221;), Ionis may notify Biogen in writing regarding Ionis&#8217; designation of such Deferred Target Development
                        Candidate and will provide Biogen the applicable Development Candidate Data Package. Within [***] days following Biogen&#8217;s receipt of the applicable Development Candidate Data Package, Biogen may designate the Accelerated Target as a
                        Collaboration Target; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided however</font>, that if Biogen designates such Accelerated Target as a Collaboration Target, in addition to any
                        credits for annual deferral fees under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.3,</u></font> Biogen may credit a pro-rated portion of the un-credited [***]% of the last annual deferral fee paid
                        to Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.2</u></font> for such Deferred Target towards the applicable milestone payment under <font style="font-size: 10pt; font-family: 'Times
                          New Roman';"><u>Section 6.2.1</u></font> (where such pro-ration will be based on the number of days between the payment of such deferral fee and the applicable designation of such Accelerated Target as a Collaboration Target,
                        divided by the lesser of 365 days and the number of days between the payment of such deferral fee and the end of the Research Term).</font></div>
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        <div><br>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">12</font></div>
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            <table cellspacing="0" cellpadding="0" id="z34194a959d1c4864949f0813e8f30836" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Biogen does not, within such [***] day period, designate the Accelerated Target as a Collaboration Target under this <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 1.8.4</u></font>, then, such Accelerated Target will no longer be a Neurology Target and Ionis and its Affiliates may work independently or with any Third Party with respect to the discovery,
                        research, development, and commercialization of ASOs (or any other compounds) targeting such Accelerated Target; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided however</font> that if
                        prior to the end of the Deferral Period originally applicable to such Accelerated Target, Ionis or any of its Affiliates enters into an agreement with a Third Party pursuant to which Ionis or its Affiliate grants such Third Party a
                        license to develop or commercialize such Deferred Target Development Candidate, Ionis will pay to Biogen [***]% of any amounts (other than Excluded Payments) received by Ionis or its Affiliate under such agreement with such Third
                        Party until such time as Ionis has reimbursed Biogen for [***]% of the last annual deferral fee paid to Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.2</u></font> for such Deferred
                        Target.</font></div>
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        <div><br>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z9358638cc1e14835a6ff806916ad538c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.9.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>End of Research Term</u></font>. At the end of the Research Term (or, with respect
                        to clauses (a), (d) and (e) in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>1.9</u></font>, the earlier termination of
                        the Core Research Program), (a) neither Ionis nor Biogen will have an obligation to perform any activities under the Core Research Program or the Neurological Disease Research Program, (b) the High Interest Target List (including
                        the ALS Targets) will be dissolved, and any Neurology Targets that have not been designated Collaboration Targets or Biogen Alternate Modality Targets will no longer be Neurology Targets under this Agreement, (c) Ionis&#8217; obligations
                        and Biogen&#8217;s rights under this Agreement with respect to such Neurology Targets and any ASOs targeting such Neurology Targets will then terminate, (d) to the extent not previously provided to Ionis during prior meetings of the
                        Neurology II JRC, at Ionis&#8217; reasonable request, Biogen will provide to Ionis any data generated under the Core Research Program and the Neurological Disease Research Program and licensed to Ionis under <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.4</u></font>&#160;and (e) to the extent not previously provided to Biogen during prior meetings of the
                        Neurology JRC, at Biogen&#8217;s reasonable request, Ionis will provide to Biogen any data generated under the Core Research Program and the Neurological Disease Research Program and licensed to Biogen under <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.3</u></font>. For clarity, the expiration of the Research Term will not affect Biogen&#8217;s rights or Ionis&#8217;
                        obligations with respect to Programs under this Agreement, including, in the case of Collaboration Programs, Ionis&#8217; obligation under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1</u></font> to use
                        Commercially Reasonable Efforts to identify a Development Candidate for each applicable Collaboration Program.</font></div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">13</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.10.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Research and Development Responsibilities</u></font>.</font></div>
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                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.10.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development Candidate Identification</u></font>.</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>ASO Development Candidate Identification Plans</u></font>. For each Collaboration
                        Program, within [***] days after the designation of each Collaboration Program, Ionis will submit to the Neurology JRC an initial draft plan to identify a Development Candidate under the applicable Collaboration Program, (such plan,
                        as may be modified from time to time to address the discovery, research and optimization activities Ionis will conduct under the applicable Collaboration Program an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
                          font-weight: bold; font-style: italic;">ASO Development Candidate Identification Plan</font>&#8221;). The Neurology JRC will review such plan and agree on a final ASO Development Candidate Identification Plan for such Collaboration
                        Program, which plan will be generally consistent with Ionis&#8217; other plans for other gene targets. Ionis will carry out its drug discovery efforts for each Collaboration Program pursuant to the applicable ASO Development Candidate
                        Identification Plan in a manner consistent with its internal practices for other gene targets with the goal of identifying a Development Candidate for the applicable Collaboration Program as soon as practicable; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that Ionis will not start work on any Equal Multi-Indication Target unless and until Ionis and Biogen have agreed on a development plan
                        and enhanced economic provisions to be paid by Biogen for Non-Neurological Indications in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>. Ionis will
                        update each ASO Development Candidate Identification Plan as needed and submit it to the Neurology JRC for its review and approval.&#160; For each Collaboration Program, Biogen will pay Ionis the milestone payment set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.1</u></font> following receipt of the applicable Design Notice.</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biomarker Work</u></font>. If the Neurology JRC agrees to include biomarker work,
                        natural history studies or endpoint development in the ASO Development Candidate Identification Plan, the [***] is responsible for performing such biomarker work taking into consideration [***].</font></div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">14</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>ASO Development Candidate Identification Term</u></font>. On a Collaboration
                        Program-by-Collaboration Program basis, the term for the conduct of the applicable ASO Development Candidate Identification Plan (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style:
                          italic;">ASO Development Candidate Identification Term</font>&#8221;) will begin on the date the applicable Neurology Target becomes a Collaboration Target and will end upon the earlier of (i) designation of a Development Candidate for
                        such Collaboration Program and (ii) the date on which Ionis notifies Biogen that, Ionis has in good faith determined that the identification of a Development Candidate under the applicable ASO Development Candidate Identification
                        Plan is no longer technically feasible under the then-current state of the art (a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Technical Failure</font>&#8221;). If Biogen disagrees
                        with Ionis&#8217; determination that a Technical Failure has occurred, it may refer the matter to an independent qualified Third Party expert accepted by both Parties for final resolution of the dispute. The expert will use the
                        information, materials and data provided to her or him by either Party to promptly resolve the dispute.&#160; The decision of the expert will be binding upon both Parties. [***] the costs of the expert.&#160; Should the Parties fail to agree
                        on the expert within [***] days following either Party&#8217;s request to nominate an expert under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1(c)</u></font>, each Party will nominate an
                        independent expert (who will not be a current or former employee of a Party or any of their Affiliates or have any personal or financial interest in a Party or any of their Affiliates), and promptly thereafter, those two independent
                        experts will agree on the Third Party expert to resolve the dispute in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1(c)</u></font>.&#160; In the event of any expert proceeding
                        under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1(c)</u></font>, Ionis will not be required to conduct the applicable ASO Development Candidate Identification Plan during the pendency of
                        such proceeding. The Parties anticipate that the last ASO Development Candidate Identification Term will end approximately [***] years after the Effective Date.</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>End of ASO Development Candidate Identification Term</u></font>. At the end of the
                        ASO Development Candidate Identification Term for a particular Collaboration Program that did not reach the Development Candidate stage, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1(e)</u></font>,
                        (i) neither Ionis nor Biogen will have an obligation to perform any activities under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10</u></font> with respect to such Collaboration Program, (ii)
                        such program will no longer be a Collaboration Program and the applicable gene target associated therewith will no longer be a Collaboration Target, (iii) Ionis&#8217; obligations and Biogen&#8217;s rights under this Agreement with respect to
                        the gene targets and any ASOs targeting such gene targets under such Collaboration Program will then terminate, (iv) to the extent not previously provided to Ionis during prior meetings of the Neurology JRC, upon Ionis&#8217; request,
                        Biogen will provide to Ionis any data generated under the Collaboration Program and licensed to Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>4.3.4</u></font>&#160;and (v) to the extent not previously provided to Biogen during prior meetings of the Neurology JRC, upon Biogen&#8217;s request, Ionis will provide to Biogen any data generated under
                        the Collaboration Program and licensed to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.3</u></font>. For
                        clarity, with respect to each Development Candidate that has reached the Development Candidate stage by the end of the ASO Development Candidate Identification Term, the expiration of the ASO Development Candidate Identification
                        Term will not affect Ionis&#8217; obligation under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.3</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.4</u></font>
                        to Develop each such Development Candidate through the completion of the first PoC Trial.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">15</font></div>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="ze8eb597d4cac469a99b52aeeb017f845" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Carryover Development Candidates</u></font>. If, by the end of the ASO Development
                        Candidate Identification Term for a particular Collaboration Program, Ionis has not designated a Development Candidate for such Collaboration Program, and at any time during the [***] period after the end of the applicable ASO
                        Development Candidate Identification Term Ionis&#8217; RMC designates an ASO discovered by Ionis that is designed to bind to the RNA that encodes the Collaboration Target for such Collaboration Program as a development candidate ready to
                        start IND-Enabling Toxicology Studies (such ASO, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Carryover Development Candidate</font>&#8221;), then, Ionis will notify Biogen and
                        will provide Biogen with the data package presented to Ionis&#8217; RMC to approve such Carryover Development Candidate. Biogen will then have [***] days from its receipt of such package to elect to enter into an amendment to this
                        Agreement under the same terms as set forth in this Agreement (except that no additional upfront payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.1</u></font> will be due). If, within [***]
                        days after Biogen&#8217;s receipt of such notice from Ionis, Biogen provides Ionis with written notice that it accepts such offer from Ionis for such Carryover Development Candidate, the Parties will execute an amendment to this Agreement
                        regarding such Carryover Development Candidate on such terms. Otherwise, Ionis will have no further obligations and Biogen will have no further rights with respect to such Carryover Development Candidate.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zd346a37acd7843a3ae0934145af03985" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.10.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Development Candidates; Initial Development Plans; Option Acceleration.</u></font></font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zc896b001ff1545d787b235ef67c4ff99" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Appointment of JDC</u></font>.<font style="font-size: 10pt; font-family: 'Times New
                          Roman'; font-weight: bold;">&#160; </font>For each Development Candidate, the CSC will appoint a Neurology JDC approximately [***] days prior to the date Ionis expects to designate a Development Candidate.&#160; Such Neurology JDC can be
                        either a new or existing Neurology JDC, but at least one of each Party&#8217;s Neurology JDC members must have the relevant disease area expertise for the particular Development Candidate.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zac1b149afdb941cf955c22d51043740b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development Candidate Data Package</u></font>.<font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>For each Collaboration Program, Ionis will notify the applicable Neurology JDC in writing within [***] days after designating a Development Candidate and will provide
                        such Neurology JDC the applicable Development Candidate Data Package.&#160;</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">16</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="z9081f05d7d544b4d9fb3a56ef671f556" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>IND-Enabling Toxicology Studies</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="ze1dd856c4f0d40c4a56d15687faa480e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">For each Development Candidate under a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, the
                        applicable Neurology JDC will agree upon a high level pre-clinical toxicology strategy no later than [***] days following its receipt of the applicable Development Candidate Data Package. Ionis will conduct the IND-Enabling
                        Toxicology Studies under such strategy to the extent consistent with the activities set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.10.2(c)</u></font>; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, if the initial strategy or applicable Initial Development Plan requires IND-Enabling Toxicology Studies that are in addition to
                        or different from the activities set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.10.2(c)</u></font>, then Biogen will pay Ionis the costs of such additional or
                        different activities to the extent such costs exceed [***]% of the costs of the activities set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.10.2(c)</u></font>. Such
                        additional costs will be Biogen-Approved Costs and will be handled in accordance with the process described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zd31aefd0132a4d448e4ce5023ccb65be" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">For each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program, the applicable Neurology JDC will agree upon a high level pre-clinical
                        toxicology strategy no later than [***] days following its receipt of the applicable Development Candidate Data Package.&#160; In addition, the applicable Neurology JDC will approve any study protocols for the IND-Enabling Toxicology
                        Studies at least [***] months prior to the anticipated commencement of such IND-Enabling Toxicology Studies. If the Neurology JDC is unable to agree on such high level pre-clinical toxicology strategy or study protocols for a
                        particular ALS Collaboration Program or Biogen Conducted Non-ALS Collaboration Program within the applicable time period as set forth above in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                            1.10.2(c)(ii)</u></font>, the matter will be referred to the CSC for resolution. If the CSC cannot agree on such a high level pre-clinical toxicology strategy within [***] days after the matter is so referred, or on any such
                        study protocol within [***] days after the matter is so referred, as applicable, then Biogen will have final decision-making authority with respect thereto for IND-Enabling Toxicology Studies conducted by Biogen. Solely with respect
                        to the first ALS Collaboration Program to have a Development Candidate, Ionis will conduct the IND-Enabling Toxicology Studies utilizing the same mechanics as set forth in <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 1.10.2(c)(i)</u></font>, and upon Initiation of such IND-Enabling Toxicology Studies Biogen will pay Ionis the applicable milestone payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                            6.5</u></font>, which IND-Enabling Toxicology Studies are complete as of the First Amendment Date for the Collaboration Program for SOD-1.&#160; Biogen will conduct, [***], all other IND-Enabling Toxicology Studies for the ALS
                        Collaboration Programs and the Biogen Conducted Non-ALS Collaboration Programs,<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"> provided</font> that Ionis may perform study analyses with respect to
                        the Biogen Conducted Non-ALS Collaboration Programs if mutually agreed by the Parties.&#160; If, with respect to a particular ALS Collaboration Program or a particular Biogen Conducted Non-ALS Collaboration Program, Biogen desires Ionis
                        to provide consulting or advisory services, and Ionis agrees to perform such services, Biogen will pay the costs of performing such services using the payment mechanisms set forth in <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 1.14.1.</u></font></font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">17</font></div>
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        </div>
        <div style="text-align: justify; margin-left: 153pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program (other than the Collaboration Program
            for [***]), provided Ionis has delivered the API to support the IND-Enabling Toxicology Studies for such Collaboration Program to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.6</u></font> at least
            [***] days prior to the anticipated commencement of IND-Enabling Toxicology Studies for such Collaboration Program (subject to Biogen&#8217;s timely delivery of an order for such API), Biogen will Initiate the first IND-Enabling Toxicology Study for
            such Collaboration Program within [***] days following Biogen&#8217;s receipt of the applicable Development Candidate Data Package. If Biogen does not Initiate the first IND-Enabling Toxicology Study for such Collaboration Program within [***] days
            following Biogen&#8217;s receipt of the applicable Development Candidate Data Package, if Ionis delivered the API to support the IND-Enabling Toxicology Studies for such Collaboration Program to Biogen under <font style="font-size: 10pt;
              font-family: 'Times New Roman';"><u>Section 1.10.6</u></font> at least [***] days prior to the anticipated commencement of IND-Enabling Toxicology Studies for such Collaboration Program, then Biogen will be deemed to have terminated this
            Agreement under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.1</u></font> solely with respect to such Collaboration Program; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided,







              however</font>, that if there is a delay in Initiating such IND-Enabling Toxicology Study caused by a condition outside of Biogen&#8217;s control (including a delay by a Third Party vendor or a delay in supply of API from Ionis from the timeline
            described in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(c)(ii)</u></font>), Biogen shall be excused from Initiating such IND-Enabling Toxicology Study for so long as such condition continues, and this
            Agreement shall not be deemed to be terminated with respect to such Collaboration Program, for so long as such condition continues.</font></div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">18</font></div>
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        </div>
        <div style="text-align: justify; margin-left: 153pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">With regard to the Collaboration Program for [***], notwithstanding any provision to the contrary in this Agreement, within [***]
            days following Biogen&#8217;s receipt of the data generated from the 13 week monkey [***] biomarker study, Biogen will notify Ionis whether it has received all necessary internal approvals to commence Development of [***]. If Biogen does not notify
            Ionis within such [***]-day period that it has received all necessary internal approvals to commence Development of [***], Biogen will be deemed to have terminated this Agreement under <font style="font-size: 10pt; font-family: 'Times New
              Roman';"><u>Section 10.2.1</u></font> solely with respect to such Collaboration Program. If Biogen notifies Ionis within such [***]-day period that it has received all necessary internal approvals to commence Development of [***], Biogen
            shall, within [***] days of the later of the date of delivery of such notice and Biogen&#8217;s receipt from Ionis of an invoice for such amount, pay Ionis an amount equal to $[***] for the API Ionis will supply to Biogen to support such
            Collaboration Program. If Biogen does not pay Ionis an amount equal to $[***] for such API within the time period described in the preceding sentence, then, if Ionis notifies Biogen in writing of such failure to pay and Biogen has not cured
            such payment failure within [***] days of such written notice, Biogen will be deemed to have terminated this Agreement under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.1</u></font> solely with respect to
            such Collaboration Program.</font></div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z99937ae67ca24ef3bb0eea0ca4d422cf" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Initial Development Plans</u></font>. For each Development Candidate under a
                        Collaboration Program, within [***] days after designation of such Development Candidate, the applicable Neurology JDC will agree on an appropriate clinical development plan for such Development Candidate through completion of the
                        first PoC Trial (each, an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Initial</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                          font-style: italic;">Development Plan</font>&#8221;). With respect to each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program, Biogen shall propose the initial draft of such Initial Development Plan to the
                        Neurology JDC for review, comment and approval. With respect to each Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, Ionis shall propose the initial draft of such
                        Initial Development Plan to the Neurology JDC for review, comment and approval. In each case, any such initial draft of an Initial Development Plan shall include the information set forth on <font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>1.10.2(d)</u></font>. If the Neurology JDC cannot agree upon the Initial
                        Development Plan for a particular Collaboration Program, the matter will be referred to the CSC for resolution. If the CSC cannot agree on the Initial Development Plan within [***] days after the matter is so referred, [***] will
                        have final decision-making authority with respect to the contents of the Initial Development Plan. In addition, prior to the Initiation of the first Clinical Study under the Initial Development Plan for a Collaboration Program, the
                        Parties will endeavor to mutually agree on a communication plan regarding the public disclosure of data and results arising from such Collaboration Program; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style:
                          italic;">provided, that</font> if the Parties cannot agree on such a communication plan, then [***] will have final decision-making authority regarding any such communications occurring prior to the License Effective Date with
                        respect to a Collaboration Program.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">19</font></div>
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        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="za76b09a974854803989d5ef009fe5f62" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Party responsible for conducting the Clinical Studies under a Collaboration Program will file and maintain the IND and other communications with Regulatory
                        Authorities for each Collaboration Program consistent with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.2.1</u></font>.&#160; Notwithstanding the foregoing, with respect to each Collaboration Program for
                        which Biogen is responsible for conducting the Clinical Studies, including each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program, Ionis shall provide such reports and/or data as reasonably requested
                        by Biogen generated from Ionis&#8217; activities performed under the applicable Initial Development Plan (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Activities Data</font>&#8221;)








                        that may be useful in support of the IND for the Development Candidate under such Collaboration Program; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, that</font>, if, after receiving
                        the Ionis Activities Data, Biogen requests that Ionis provide Biogen with additional information outside of the scope of the Ionis Activities Data that Biogen reasonably believes is necessary or useful to support the IND, then, to
                        the extent such additional information is in Ionis&#8217; possession and delivering such data to Biogen will not breach any obligation Ionis owes to a Third Party, Ionis will promptly deliver such additional information to Biogen solely
                        for Biogen to use to support the IND.&#160; [***] will bear the cost of the transfer of such additional information to Biogen pursuant to the preceding sentence; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style:
                          italic;">provided</font>, that if [***] would incur out-of-pocket costs in excess of $[***] or FTE Costs in excess of the equivalent of [***] for one FTE at the then-applicable Ionis FTE Rate in connection with the delivery of
                        such additional information, then [***] shall reimburse [***] for such excess.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="ze388fcfd548648f0bc5e4c6a9e6afbbd" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If the requirements of the Phase 1 Trial Design for a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program
                        require (i) more than [***] human subjects, including single ascending dose and multiple ascending dose arms, or (ii) dosing longer than [***], then Ionis may elect to either (1) conduct such larger or longer Phase 1 Trial (in which
                        case <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font> will apply), or (2) have Biogen conduct such Phase 1 Trial.&#160; If Ionis elects to have Biogen conduct such Phase 1 Trial, then Biogen
                        will conduct the Phase 1 Trial with Ionis&#8217; reasonable cooperation and in lieu of the applicable milestone payment payable to Ionis pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.4</u></font>
                        (as calculated in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>) with respect to such Phase 1 Trial, Biogen will pay Ionis a milestone payment equal to $[***].</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">20</font></div>
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        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z64c90d98957e4fba952f58d588f46869" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If the Initial Development Plan relates to an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, then Biogen will conduct the Phase 1 Trial
                        and will pay Ionis a milestone payment in the amount as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 2</u></font> of <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 6.5</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 1</u></font> of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section








                            6.4</u></font>, as applicable.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z024ff936f0e74ec7b7d8cacdff3af6a6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iv)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Based on such Initial Development Plan, the CSC will update <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 5.1.4</u></font>
                        to add Specific Performance Milestone Events related to Biogen&#8217;s Development and Commercialization of the Development Candidate after the License Effective Date with respect to a Collaboration Program, which Specific Performance
                        Milestone Events will be generally consistent with Biogen&#8217;s development timelines for its other drug development programs of similar stage and market potential.&#160; If the CSC cannot unanimously agree upon the Specific Performance
                        Milestone Events for a particular Collaboration Program within [***] days after the date the CSC started discussing such Specific Performance Milestone Events, the matter will be referred to expert resolution pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1.4</u></font>. Ionis will update each Initial Development Plan as needed, but at least once Annually, and submit it to the applicable Neurology JDC for its
                        review and approval. If the applicable Neurology JDC cannot agree on the contents of any updated Initial Development Plan, the matter will be resolved in accordance with the procedures for establishing the Initial Development Plan
                        set forth in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(d)</u></font>.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z1c623b43b8494cc3a89f2155603dbc6c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(v)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The study synopsis for each Clinical Study for a Collaboration Program other than an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program shall
                        be agreed on by the applicable Neurology JDC no later than [***] months prior to the anticipated Initiation of such Clinical Study, and shall contain the information set forth on <font style="font-size: 10pt; font-family: 'Times
                          New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>1.10.2(d)(v)</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant:
                          small-caps;">&#160;</font>with respect to the applicable Clinical Study<font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;">.</font></font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">21</font></div>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zc0c296fc648049f9af58a3e160431786" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Cost Estimates</u></font>. After designation of a Development Candidate under a
                        Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, the applicable Neurology JDC will agree on an initial estimate of the expected cost for Ionis to conduct the work
                        [***] specified in the applicable Initial Development Plan, including Ionis&#8217; expected [***] and [***] costs (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Cost
                          Estimate</font>&#8221;). The initial Cost Estimate [***] shall be agreed on by the applicable Neurology JDC no later than [***] months prior to the anticipated [***]. Based on the Cost Estimates, the Neurology JDC will establish the
                        [***] and [***] milestone payments for such Collaboration Program, which payments will be equal to (i) [***]; plus (ii) [***]. The Parties will promptly negotiate in good faith using the Ionis/Biogen Additional Agreements as a basis
                        for Cost Estimates and, if the total milestone payment [***] is more than $[***], the Parties will apportion such total milestone payment into smaller milestone payments in accordance with <font style="font-size: 10pt; font-family:
                          'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>1.10.2(e)</u></font>; <font style="font-size: 10pt; font-family: 'Times New Roman';
                          font-style: italic;">provided, however</font>, that if [***], then the Neurology JDC shall determine whether and how to apportion such total milestone payment into smaller milestone payments.<font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">&#160;</font>Each such smaller milestone payment shall be payable by Biogen within [***] days after receipt of the applicable invoice by Biogen following the event
                        that triggered such milestone payment. If the total milestone payment [***] is $[***] or less, then such milestone payment shall become due in its entirety upon [***], and shall be payable by Biogen within [***] days after receipt
                        of the applicable invoice by Biogen following [***]. As part of this process, Ionis will provide the Neurology JDC with a good faith estimate of the cost to conduct the work necessary to develop such Development Candidates under the
                        applicable Initial Development Plan using a similar methodology as used under the Ionis/Biogen Additional Agreements. [***] months prior to the [***], using the process set forth above, the Neurology JDC will re-assess the total
                        cost of such [***] and, if the cost has changed from the initial Cost Estimate, the Neurology JDC will adjust the applicable milestone payment accordingly, with any such adjustment to be agreed in writing to no later than the date
                        that is [***] months prior to the [***]. Once there is less than [***] months prior to the [***], or such [***], if there are any changes to such [***] in accordance with this Agreement that result in an increase to the cost of such
                        [***], then (A) if such cost is increased by more than [***], such increased costs will constitute an additional milestone payment to be paid in accordance with the provisions of this <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 1.10.2(e)</u></font>, or (B) if such cost is increased by [***], such increase will not affect the milestone payments for such [***] established under this <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 1.10.2(e)</u></font>, but instead will be handled in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>.&#160; For clarity, with respect to any
                        increase in the cost of a [***] by more than [***]% under clause (A) of the preceding sentence, if such increased costs total $[***] or less and such [***], then such increased costs shall become due in their entirety immediately,
                        and shall be payable by Biogen within [***] days after receipt of the applicable invoice by Biogen. If the Neurology JDC cannot agree on the Cost Estimates within [***] days of receiving the proposed Cost Estimate, the matter will
                        be referred to the CSC for resolution. Once the Neurology JDC has agreed on a Cost Estimate and/or the [***] milestone payments for such Collaboration Program are established under this <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 1.10.2(e)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>, such agreement will be documented in a written side letter, in the form and
                        format attached hereto as <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 4</u></font>, which shall be executed by both Parties.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">22</font></div>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z4c0f02bd4c834184a3c4f4216803c413" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Obligation to Start Development Activities</u></font>. Ionis will not be required
                        to conduct any Development activities for a Development Candidate if the Initial Development Plan, Specific Performance Milestone Events and the corresponding Cost Estimates have not been agreed to pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2</u></font>.&#160; Prior to such time as the Parties mutually agree on such Cost Estimate and/or the applicable [***] milestone payments and have executed a
                        written side letter with respect to the foregoing in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>, Ionis may, in its discretion, commence Development activities for
                        which it is responsible under this Agreement; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Biogen will not be responsible for any costs of such Development
                        activities if commenced by Ionis prior to the execution of any such side letter unless and until such a side letter has been executed by the Parties, and in no event will Biogen be responsible for any amounts incurred by Ionis for
                        such Development activities in excess of amounts set forth in the side letter executed by the Parties with respect to such Development activities.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zf28aa64397f44fb1b65ae04eb9111b1f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(g)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Option Acceleration</u></font>. If the PoC Trial for a Collaboration Program that
                        is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program will be [***] or more, or require more than [***], then, if Ionis provides to Biogen the notice described in the following sentence, Ionis will
                        not be required to conduct such PoC Trial for such Collaboration Program.&#160; Ionis will notify Biogen within [***] after finalization of the initial PoC Trial Design pursuant to <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 1.10.2(d)</u></font> (or each time there is a material change thereto) for a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program if Ionis elects
                        not to conduct such PoC Trial for such Collaboration Program (such notice, an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Acceleration Notice</font>&#8221;). If Ionis has
                        delivered an Option Acceleration Notice as provided in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(g)</u></font>, Biogen will have [***] from its receipt of the data generated under the
                        [***] for the first Phase 1 Trial for such Collaboration Program (an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Acceleration Deadline</font>&#8221;) to exercise its Option
                        for the applicable Collaboration Program.&#160; If Biogen does not exercise its Option for the applicable Collaboration Program by the applicable Option Acceleration Deadline, Biogen&#8217;s Option under <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 3.1</u></font> with respect to such Collaboration Program will expire and such Collaboration Program will terminate.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">23</font></div>
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        </div>
        <div style="text-align: justify; margin-left: 117pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">After Biogen&#8217;s receipt of an Option Acceleration Notice with respect to a particular Collaboration Program, the Parties will
            mutually agree on the contents of all correspondence with and submissions to Regulatory Authorities to the extent related to the PoC Trial for the applicable Collaboration Program; <font style="font-size: 10pt; font-family: 'Times New Roman';
              font-style: italic;">provided, however</font>, that if the Parties cannot so mutually agree, then [***] will have final decision-making authority but will not deliver any correspondence to Regulatory Authorities related to the PoC Trial for
            the applicable Collaboration Program that is not mutually agreed by the Parties unless [***] determines such correspondence is required to be delivered and cannot be delayed.</font></div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z78be0837e4a345ef9ab72870c8cfcf87" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(h)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Attaching Plans to Neurology JDC Minutes</u></font>. The Neurology JDC will attach
                        each Initial Development Plan and, if applicable, associated Cost Estimates to the minutes of the Neurology JDC for the meeting at which such Initial Development Plan and, if applicable, Cost Estimates were agreed. For clarity, such
                        Initial Development Plan and Cost Estimates need not be agreed to at the same meeting of the Neurology JDC.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z198d298c3f424620a823384821006b24" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.10.3.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development Term</u></font>. The term for the conduct of the Drug Development
                        Program will begin on the designation of the first Development Candidate and will end upon the earlier of (a) completion of the Initial Development Plans under all Collaboration Programs, which the Parties estimate will be
                        approximately [***] years after the Effective Date, (b) exercise by Biogen of its Option for all Collaboration Programs, (c) the termination of the last Collaboration Program and (d) mutual agreement of the Parties to terminate the
                        Drug Development Program.</font></div>
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            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z1e28f06a372647b78499bcc7397c5cb3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.10.4.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Drug Development</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zeb2fb8506df24fde84cc4aff44a0133d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Collaboration Programs Other than ALS Collaboration Programs
                            and Biogen Conducted Non-ALS Collaboration Programs</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">.</font>&#160; For each Collaboration Program that is not an ALS Collaboration Program or
                        a Biogen Conducted Non-ALS Collaboration Program, Ionis will use Commercially Reasonable Efforts to conduct all activities under each Initial Development Plan on the timeline set forth in the applicable Initial Development Plan. For
                        each Biogen Conducted Non-ALS Collaboration Program, Ionis will use Commercially Reasonable Efforts to conduct all activities allocated to Ionis under each Initial Development Plan on the timeline set forth in the applicable Initial
                        Development Plan. Without limiting the foregoing, Ionis may discontinue Development under an Initial Development Plan if after having consulted, and having given good faith consideration to the recommendations of the Neurology JDC
                        and a mutually-agreed Third Party expert, Ionis in good faith believes that continuing such Development would (i) pose an unacceptable risk or threat of harm in humans, or (ii) violate any Applicable Law, ethical principles, or
                        principles of scientific integrity. Prior to discontinuing Development under an Initial Development Plan, Ionis will provide Biogen with reasonable advance notice of such discontinuation, including the grounds for Ionis&#8217;
                        determination. If Ionis elects to discontinue Development under an Initial Development Plan pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.4(a)</u></font>, Biogen may, in its
                        discretion, elect to continue Development of the applicable Development Candidate by providing Ionis with written notice of Biogen&#8217;s exercise of the Option within [***] after Ionis&#8217; written notice to Biogen of such discontinuation
                        and [***]. If Biogen does not timely exercise its Option under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.4(a)</u></font>, then the Option will expire.</font></div>
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        <div><br>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">24</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="z721e037a44fb473e956dc73e1a8d161d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>Phase 1 Trials</u></font>. Each Phase 1<font style="font-size:
                          10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>Trial will be conducted in accordance with the applicable Phase 1 Trial Design set forth in the applicable Initial Development Plan.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z87252b0f182047c4b51b65e80d80a3a5" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">At meetings of the applicable Neurology JDC and at other times as appropriate, Ionis will keep Biogen informed of the progress and status of each Phase 1 Trial
                        conducted by Ionis. When [***] under a Phase 1 Trial, Ionis will notify Biogen in writing of such [***] within [***] days of the conclusion of such Phase 1 Trial. Ionis will provide Biogen with the data generated under the [***] for
                        such Phase 1 Trial as soon as practicable after such notice.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z8e0c41f08e194baa87c487f639fbb2d6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Biogen conducts a Phase 1 Trial for a Collaboration Program, including an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, at meetings
                        of the applicable Neurology JDC and at other times as appropriate, Biogen will keep Ionis informed of the progress and status of such Phase 1 Trial. When Biogen [***] a Phase 1 Trial, Biogen will notify Ionis in writing of such
                        [***] within [***] days of the conclusion of such Phase 1 Trial. Biogen will provide Ionis with the data generated under the [***] for such Phase 1 Trial as soon as practicable after such notice.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">25</font></div>
          <div id="DSPFPageBreak" style="page-break-after:always;">
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        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z32d46b2b61164a3c91c647886510fc79" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><u>PoC Trial</u></font>. Each PoC<font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>Trial will be conducted in accordance with the PoC Trial Design set forth in the applicable Initial Development Plan.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zf9a639903d0844e5868fa90b135e5d33" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">At meetings of the applicable Neurology JDC and at other times as appropriate, Ionis will keep Biogen informed of the progress and status of each PoC Trial conducted by
                        Ionis. When Ionis [***] a PoC Trial under the applicable Initial Development Plan, Ionis will notify Biogen in writing within [***] days after such [***]. Ionis will provide Biogen with the [***] as soon as practicable after such
                        notice.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z927512b650b145378238ac3423a13dfe" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Biogen conducts a PoC Trial for a Collaboration Program, including an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, then at meetings
                        of the applicable Neurology JDC and at other times as appropriate, Biogen will keep Ionis informed of the progress and status of the PoC Trial for such Collaboration Program. When Biogen completes such PoC Trial, Biogen will notify
                        Ionis in writing within [***] days after such completion, and will provide Ionis with [***] as soon as practicable after such notice.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zeb319627367648d68f4ae108222049e8" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.10.5.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Briefing the Neurology JRC, Neurology JDC and CSC; Conduct of Research and
                            Development</u></font>. At each regularly scheduled meeting of the Neurology JRC, the Parties will provide progress updates on (a) the Neurological Disease Research Program and progress toward achieving Target Sanction for each
                        High Interest Target and progress related to ALS Targets, (b) activities conducted under the Core Research Program, (c) progress under each ASO Development Candidate Identification Plan toward designating a Development Candidate,
                        (d) activities on the Deferred Targets conducted pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.4</u></font> and (e) the progress of any Ionis Neurology Targets (including the estimated
                        time for each Ionis Neurology Target to achieve Target Sanction), in each case, together with a summary of data associated with each Party&#8217;s research and/or Development activities for each Collaboration Program. At each Neurology
                        JDC meeting, the Parties will provide progress updates on activities conducted under the Initial Development Plans for the applicable Development Candidates, together with a summary of data associated with each Party&#8217;s Development
                        activities for the applicable Collaboration Program. At each CSC meeting, the Parties will provide any information reasonably requested by the members of the CSC in advance of such meeting.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">26</font></div>
          <div id="DSPFPageBreak" style="page-break-after:always;">
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        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zb65ec442cc3d4cda82056a481c78a858" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.10.6.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Clinical Supplies by Ionis</u></font>. For Collaboration Programs that are not ALS
                        Collaboration Programs or Biogen Conducted Non-ALS Collaboration Programs, Ionis, at its expense, will supply API (on its own or through a CMO approved by Biogen) and Clinical Supplies to support the Research and Development
                        activities under each Neurology Plan through the License Effective Date with respect to a Collaboration Program. If Biogen exercises an Option for a Collaboration Program that is not an ALS Collaboration Program or a Biogen
                        Conducted Non-ALS Collaboration Program at least [***] prior to the planned Initiation of the PoC Trial for the applicable Collaboration Program, Biogen may elect to either have (a) Ionis supply Clinical Supplies for such PoC Trial
                        (on its own or through a CMO approved by Biogen), in which case Biogen will pay Ionis an amount equal to [***] or (b) a CMO supply Clinical Supplies for such PoC Trial in accordance with the Manufacturing Agreement entered into with
                        such CMO. If Biogen exercises an Option for a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program prior to, but less than [***] before, the planned Initiation of the PoC
                        Trial for the applicable Collaboration Program, Ionis will supply Clinical Supplies for such PoC Trial (on its own or through a CMO approved by Biogen) and Biogen will pay Ionis an amount equal to [***]. For ALS Collaboration
                        Programs and Biogen Conducted Non-ALS Collaboration Programs, Ionis will supply API (on its own or through a CMO approved by Biogen) for clinical purposes in accordance with <font style="font-size: 10pt; font-family: 'Times New
                          Roman'; font-variant: small-caps;"><u>Schedule 1.10.6</u></font>, and such supply will be at Biogen&#8217;s expense using the mechanism set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>,
                        and Biogen will be responsible for all other aspects of Clinical Supply for such clinical activities.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zc46dadf3bb3a4b54affc684508d77573" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.10.7.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Collaborations with Academics and Non-Profit Institutions</u></font>. Each Party
                        (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Contracting Party</font>&#8221;) may engage one or more academic or non-profit institutions to conduct work under any Neurology
                        Plan or on any High Interest Target, Collaboration Target or Deferred Target, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>, <font style="font-size: 10pt; font-family: 'Times
                          New Roman'; font-style: italic;">however</font> that with respect to any such academic or non-profit institution engaged to conduct such activities with respect to a High Interest Target, Collaboration Target or Deferred Target
                        where such engagement begins after the date such High Interest Target, Collaboration Target or Deferred Target is placed on the High Interest Target List or designated, as applicable, (a) the Contracting Party shall provide the
                        other Party with an opportunity to comment on the proposed terms of any agreement or amendment to an existing agreement to be entered into with such institution, and (b) so long as the other Party provides the Contracting Party such
                        comments within [***] days after receiving a draft of such agreement from the Contracting Party, the Contracting Party will [***].&#160; The Contracting Party will not be responsible for [***] as a result of the other Party&#8217;s [***] to
                        the terms of any agreement with any such academic or non-profit institution.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z4bbd2bc9443c4c218a64d10906e03e91" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.11.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Resource Allocations</u></font>. During the first [***] following the Effective
                        Date, Ionis will use Commercially Reasonable Efforts to build a team of [***] FTEs to perform the activities under the Core Research Plan, the Neurological Disease Research Plan, and the target validation activities contemplated
                        under <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font>; and thereafter until the sixth anniversary of the Effective Date, Ionis will dedicate [***] FTEs to
                        perform such activities; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>, Ionis may utilize such number of such [***] FTEs to perform drug discovery activities on ALS Targets as
                        agreed by the Neurology JRC. At all times during such period, such FTEs will have experience and qualifications similar to that of the FTEs initially assigned to perform such activities hereunder. Biogen will be responsible for
                        devoting its resources toward specific research efforts under the Core Research Program and Neurological Disease Research Program as reasonably determined by Biogen. During the [***] after the Effective Date, [***] of Ionis&#8217; [***]
                        FTEs will be allocated to activities focused on core technology research and the Neurology JRC will determine the appropriate allocation of resources thereafter. Ionis will update the Neurology JRC at each meeting thereof on the
                        utilization of such FTEs and provide the Neurology JRC with summaries of resource and FTE utilization in a format mutually agreed to by each Party&#8217;s Alliance Managers. Biogen may also choose to supplement Ionis&#8217; efforts under the
                        Core Research Plan and the Neurological Disease Research Plan with its own scientists at various points throughout the Research Term. After the sixth anniversary of the Effective Date, Ionis will provide sufficient resources to
                        perform its obligations under each Collaboration Program as reasonably determined by Ionis.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">27</font></div>
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        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zcf404e268e6446ee91b14407a6d320ee" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.12.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Research and Development Costs Paid by Ionis.</u></font></font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zc321f8842daa46558db28979fc34545c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.12.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Research Programs</u></font>. During the Research Term, Ionis will be responsible
                        for all Ionis Activities under the Core Research Program and the Neurological Disease Research Program, and all costs and expenses associated therewith.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z4e0735c468d341008764257c947f54bd" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.12.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Collaboration Programs</u></font>. During the Option Period, on a Collaboration
                        Program-by-Collaboration Program basis, Ionis will be responsible for all Ionis Activities under the ASO Development Candidate Identification Plan and the Initial Development Plan and, except as otherwise provided under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.13.1</u></font>, all costs and expenses associated therewith.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z972a898148074865b678dfe74b238120" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.13.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Research and Development Costs Paid by Biogen</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z273ccff6f64d4fa0ba61bb28ac48dfe7" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.13.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Before </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>the











                            License Effective Date</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z49699c2476b940cabe507a374378a9f9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Research Programs</u></font>. During the Research Term, Biogen will be responsible
                        for all Biogen Activities under the Core Research Program and Neurological Disease Research Program, and all costs and expenses associated therewith.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z1288fb79823a4a97afd1fc1927b16462" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Collaboration Programs</u></font>. During the Option Period, on a Collaboration
                        Program-by-Collaboration Program basis, Biogen will be responsible for any Biogen Activities under the ASO Development Candidate Identification Plan and the Initial Development Plan and all costs and expenses associated therewith.
                        In addition, Biogen will be responsible for paying any Biogen-Approved Costs resulting from Biogen-Approved Changes using the payment mechanisms set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                            1.14</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">28</font></div>
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        <div style="text-align: justify;">
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            <table cellspacing="0" cellpadding="0" id="z9b2c972de65c4daf932144a3eedb71fd" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Additional Activities Approved by Biogen</u></font>. If, with respect to a
                        particular Collaboration Program, Biogen desires that either Ionis or a Third Party [***] or conduct other work to support Approval of a Collaboration Product, including [***], prior to the License Effective Date, and Ionis agrees
                        to perform such work, Biogen will pay the costs of conducting such work using the payment mechanisms set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>.</font></div>
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                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.13.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>After </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';
                          font-weight: bold;"><u>the License Effective Date</u></font>. After the License Effective Date with respect to the applicable Collaboration Program, Biogen will be solely responsible for the costs and expenses related to the
                        Development, Manufacture and Commercialization of Collaboration Products, including any work performed by Ionis at Biogen&#8217;s request, and all supply chain planning and decision-making.</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.14.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Payment Mechanisms</u></font>.</font></div>
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                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.14.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Payment Mechanics for Additional Activities Approved by Biogen</u></font>.&#160; Biogen
                        will pay Ionis (A) costs resulting from requests from Biogen that Ionis perform additional work under this Agreement, including, the cost of Ionis&#8217; time incurred in performing such work at the then-applicable Ionis FTE Rate (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">FTE Costs</font>&#8221;), the cost of [***], and any [***] incurred by Ionis in performing such work, or (B) Additional Plan Costs resulting
                        from Biogen-Approved Changes (such costs, collectively &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen-Approved Costs</font>&#8221;). For clarity, the Biogen-Approved Costs
                        shall include Additional Plan Costs for a [***] that result from changes to such [***] made after the milestone payment with respect to such [***] is agreed upon in writing by the Parties pursuant to <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>, if such cost is increased by [***] as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>).&#160; For the
                        avoidance of doubt, if such cost is increased by more than [***] as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>), such increased costs will constitute an additional
                        milestone payment to be paid in accordance with the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>, and will not be handled under this <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>.&#160; Ionis will permit Biogen to review, negotiate (with Ionis) and approve (including through the Neurology JDC) all Biogen-Approved Costs; <font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-style: italic;">provided</font> Biogen will provide a substantive, good faith response within [***] days of Ionis&#8217; request for approval.&#160; For clarity (1) this <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 1.14.1</u></font> will not be used to establish the initial milestone payments under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>, and
                        (2) expenses paid under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1(a)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1(b)</u></font> are not
                        subject to reconciliation. Once Biogen-Approved Costs are mutually agreed under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>, such agreement will be documented in a written side
                        letter, in the form and format attached hereto as <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 4</u></font>, which shall be executed by both Parties. Prior to such time as the
                        Parties mutually agree on such Biogen-Approved Costs and have executed a written side letter with respect to the foregoing, Ionis may, in its discretion, commence Development activities for which it is responsible under this
                        Agreement; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Biogen will not be responsible for any costs of such Development activities if commenced by Ionis prior to
                        the execution of any such side letter unless and until such a side letter has been executed by the Parties, and in no event will Biogen be responsible for any amounts incurred by Ionis for such Development activities in excess of
                        amounts set forth in the side letter executed by the Parties with respect to such Development activities.</font></div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">29</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">For Biogen-Approved Costs resulting from [***], or from [***] that are made after the milestone payment with respect to such [***] is agreed upon in writing by the
                        Parties pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>, Biogen will pay Ionis for such Biogen-Approved Costs [***] within [***] days after receipt of the applicable
                        invoice by Biogen following [***], or the date that Biogen agrees to such changes to such [***], as applicable; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that if
                        such Biogen-Approved Costs total more than $[***], the Parties will apportion such total Biogen-Approved Costs into smaller milestone payments in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';
                          font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>1.10.2(e)</u></font> (or, if such Biogen-Approved Costs result from changes to a [***], then the Neurology JDC
                        shall determine whether and how to apportion such Biogen-Approved Costs into smaller milestone payments).&#160; Each such smaller milestone payment shall be payable by Biogen within [***] days after receipt of the applicable invoice by
                        Biogen following the event that triggered such milestone payment.&#160; If such Biogen-Approved Costs total $[***] or less, then such Biogen-Approved Costs shall become due in their entirety upon [***] or the date that the Parties agree
                        to such Biogen-Approved Costs, if such [***], and shall be payable by Biogen within [***] days after receipt of the applicable invoice by Biogen following [***] or the date of such agreement regarding the Biogen-Approved Costs, as
                        applicable.</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">For Biogen-Approved Costs resulting from [***], Biogen will pay Ionis, in accordance with any applicable [***] entered into by the Parties after the Effective Date, for
                        [***]% of such Biogen-Approved Costs within [***] days after receipt of the applicable invoice by Biogen following Biogen&#8217;s request or approval for such [***], and the remaining [***]% within [***] days after receipt of the
                        applicable invoice by Biogen following [***].</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">For any Biogen-Approved Cost that (i) has an Estimated Biogen-Approved Cost of less than $[***] and (ii) does not result from [***], from [***] that are made after the
                        milestone payment with respect to such [***] is agreed upon in writing by the Parties pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font> or from [***], Ionis will invoice
                        Biogen directly for such Biogen-Approved Cost in advance, on a [***] basis based upon the applicable Estimated Biogen-Approved Costs and Biogen will pay the invoices submitted pursuant to this <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 1.14.1(c)</u></font> for such Biogen-Approved Costs within [***] days after receipt of the applicable invoice by Biogen.&#160; For purposes of this <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 1.14.1(c)</u></font>, &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Measurement Period</font>&#8221; means each [***].</font></div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">30</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">For any Biogen-Approved Costs that (i) has an Estimated Biogen-Approved Cost of $[***] or more and (ii) does not result from [***], from [***] that are made after the
                        milestone payment with respect to such [***] is agreed upon in writing by the Parties pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font> or from [***], Ionis will invoice
                        Biogen directly for such Biogen-Approved Cost in advance on a [***] basis based upon the applicable Estimated Biogen-Approved Costs and Biogen will pay the invoices submitted pursuant to this <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 1.14.1(d)</u></font> for such Biogen-Approved Costs within [***] days after receipt of the applicable invoice by Biogen.&#160; For purposes of this <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 1.14.1(d)</u></font>, &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Measurement Period</font>&#8221; means each [***].</font></div>
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          <div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Within [***] days after the end of the applicable Measurement Period, Ionis will provide Biogen with a written statement (i) reconciling the [***] the Estimated
                        Biogen-Approved Costs and the [***] within the Biogen-Approved Costs (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Actual Biogen-Approved Costs</font>&#8221;) incurred by Ionis
                        during the just-ended Measurement Period and (ii) confirming that the FTE Costs portion of the Estimated Biogen-Approved Costs is a reasonable approximation of the actual FTE Costs incurred by Ionis during the just-ended Measurement
                        Period. If the Estimated Biogen-Approved Costs exceed the Actual Biogen-Approved Costs for such period, Ionis will, offset all such excess payments against any future invoices under this Agreement until Biogen has recouped all such
                        overpayments.&#160; If the Estimated Biogen-Approved Costs are less than the Actual Biogen-Approved Costs for such period, Ionis will invoice Biogen for the remaining amounts owed to Ionis, and Biogen will pay such invoices within [***]
                        days of receipt of such invoice. In the case where additional activities under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font> are performed by a Third Party, the Parties will
                        arrange for the Third Party to directly bill Biogen and for Biogen to pay such Third Party directly.</font></div>
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            <table cellspacing="0" cellpadding="0" id="z837f6b7dfc0d4acda89e70d58dff5b6d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.15.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Participation in Regulatory Meetings</u></font>. For each Collaboration Program,
                        each Party will conduct its interactions and communications with Regulatory Authorities in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.2</u></font>.</font></div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">31</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.16.</font></td>
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                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Participation in Meetings Sponsored by a Party&#8217;s Clinical Development Group</u></font>.
                        With respect to each Collaboration Program (including each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program), each Party will provide the other Party with an invitation to attend, and allow such
                        other Party to participate in, any meetings sponsored by a Party&#8217;s clinical development group relating to the Development Candidate or the conduct or design of any Clinical Study; <font style="font-size: 10pt; font-family: 'Times
                          New Roman'; font-style: italic;">provided, however</font>, that such first Party may exclude the other Party from any portions of such meetings that do not pertain to such Development Candidate or all of any such meeting if such
                        Party determines that it is not feasible for the other Party to attend any such meeting because other products or matters will be discussed in combination with the Development Candidate at such meeting; and <font style="font-size:
                          10pt; font-family: 'Times New Roman'; font-style: italic;">provided, further</font>, that, the organizing Party will endeavor to structure such meetings that discuss topics unrelated to the Development Candidate in a manner that
                        permits the non-organizing Party to attend (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>, structuring the agenda of such meeting so that the Development Candidate is discussed first so that the
                        non-organizing Party may attend that portion of such meeting only). With respect to any such meetings organized by a Party, the non-organizing Party shall comply with the organizing Party&#8217;s internal policies disclosed to the
                        non-organizing Party regarding attendance and participation in such meetings, and the non-organizing Party will participate in such meeting in a manner that is consistent with the organizing Party&#8217;s strategy for the applicable
                        Development Candidate. If a Party is excluded from any such meeting, the organizing Party will provide such Party with a written summary of the portions of such meeting relevant to such Development Candidate within [***] days after
                        such meeting. For the avoidance of doubt, this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.16</u></font> shall not apply to unplanned meetings or unplanned discussions with investigators or key
                        opinion leaders. Biogen&#8217;s obligation under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.16</u></font> to invite Ionis to attend and participate in any meetings organized by Biogen will cease, on
                        a Collaboration Product-by-Collaboration Product basis, on the date Biogen submits an NDA or MAA to a Regulatory Authority for such Collaboration Product.</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.17.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Impact of [***] Development Path</u></font>. If the Parties mutually agree to amend
                        an Initial Development Plan for a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, where such amended plan contemplates [***], then the Parties will make appropriate
                        changes to the operational terms of this Agreement (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>, [***]) to reflect such [***] development plan, consistent with the comparable provisions
                        necessary to support the development plan under the [***]; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>, that if the Initial Development Plan for a Biogen Conducted Non-ALS
                        Collaboration Program contemplates such [***] development path, then the Parties will determine by mutual agreement prior to commencing any [***] under such Initial Development Plan whether to designate such [***] for such Biogen
                        Conducted Non-ALS Collaboration Program. Nothing in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.17</u></font> will affect either Party&#8217;s rights or obligations under <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(g)</u></font>.</font></div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">32</font></div>
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.18.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Research and Development Management</u></font>.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zc1871c7d413e40d7b93bb3e377e98457" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.18.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Collaboration Steering Committee</u></font>. The Parties will establish a
                        Collaboration steering committee (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">CSC</font>&#8221;) with the powers, roles and responsibilities set forth on <font style="font-size:
                          10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 1.18.1</u></font> and in this <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 1.18.1</u></font> to oversee the Collaboration. The CSC will consist of up to three representatives appointed by Ionis and up to three representatives appointed by Biogen. The Neurology JRC and
                        Neurology JDC under this Agreement will report to the CSC. The CSC will determine the CSC operating procedures at its first meeting, including the CSC&#8217;s policies for replacement of CSC members, policies for participation by
                        additional representatives or consultants invited to attend CSC meetings, and the location of meetings, which will be codified in the written minutes of the first CSC meeting. Each Party will be responsible for the costs and
                        expenses of its own employees or consultants attending CSC meetings. Any decision that may be made by the Neurology JRC or Neurology JDC may be made by the CSC and such decision by the CSC will have the same effect as if made by the
                        Neurology JRC or the Neurology JDC under this Agreement. The CSC may delegate any of its functions specified in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.1(a)</u></font> below to a Neurology JDC
                        by agreeing to and codifying such delegation in the minutes of the CSC.</font></div>
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          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z5fc55736163f4ad4b90bb997e2e48ba5" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Role of the CSC</u></font>. Without limiting any of the foregoing, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.4</u></font>, the CSC will perform the following functions, some or all of which may be addressed directly at any given CSC meeting:</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zdbcd056c9aa94bad95181d385099b7d9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">approving the terms on which Biogen would develop and commercialize a Multi-Indication Product as described in <font style="font-size: 10pt; font-family: 'Times New
                          Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z801dbae41e5c4367ad6e09d790b3c73f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">determining the primary disease association of a Multi-Indication Target;</font></div>
                  </td>
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          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z717fc92d1c284f71984dd831a189f2da" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">appointing a Neurology JDC for each Development Candidate under this Agreement, whether by creating a new Neurology JDC or assigning an existing Neurology JDC to
                        oversee such Development Candidate;</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z922d4ca9538646f58b8c7d3a68182b67" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iv)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">establishing the Initial Development Plan in the event of a Neurology JDC dispute as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                            1.10.2(d)</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z9ff1883b2d834ae68414a224a4ea5a46" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(v)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">establishing the Specific Performance Milestone Events as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(d)(iv)</u></font>;</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">33</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="zf40d66a91f4c4870bd1617becf846fd2" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(vi)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">establishing the [***] and [***] milestone payments if the Neurology JDC is unable to agree on such payments as described in <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 1.10.2(e)</u></font>;</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z52b2bbf94fa747f79308d97940c48a15" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(vii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">reviewing and assessing reports provided by the Neurology JRC and the Neurology JDCs;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z611e7c93295b4e048120a58b42d17eec" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(viii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">providing input to the JPC as appropriate;</font></div>
                  </td>
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          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z7447f4d0d16041489e4a2d278797a0fb" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ix)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">reviewing and providing input on the CTDs and IDPs as appropriate;</font></div>
                  </td>
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          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z418a2f79ea784d5e84ca5e8230607b61" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(x)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">assisting with and participating in the resolution of disputes as contemplated in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1.1</u></font>;
                        and</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z12c85fd41b26466e9bd31839a08100ea" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(xi)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">such other review and advisory responsibilities as may be assigned to the CSC by the Parties pursuant to this Agreement.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zea6e9152161a461f835a52fc12efd870" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.18.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Neurology JRC</u></font>. The Parties will establish a joint research committee
                        (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurology JRC</font>&#8221;) reporting to the CSC, to provide advice and make recommendations on the conduct of activities under
                        the Core Research Program, Neurological Disease Research Program and each Collaboration Program up to Development Candidate designation. The Neurology JRC will consist of up to three representatives appointed by Ionis and up to
                        three representatives appointed by Biogen. Each Neurology JRC member will have experience and expertise appropriate for the Core Research Program, Neurological Disease Research Program and/or the stage of development of the
                        Collaboration Programs. Each Party will designate one of its representatives who is empowered by such Party to make decisions related to the performance of such Party&#8217;s obligations under this Agreement to act as the co-chair of the
                        Neurology JRC. The co-chairs will be responsible for overseeing the activities of the Neurology JRC consistent with the responsibilities set forth below in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                            1.18.2</u></font>. <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 1.18.2</u></font> sets forth
                        certain Neurology JRC governance matters agreed to as of the Effective Date. The Neurology JRC will determine the Neurology JRC operating procedures at its first meeting, including the Neurology JRC&#8217;s policies for replacement of
                        Neurology JRC members, policies for participation by additional representatives or consultants invited to attend Neurology JRC meetings, and the location of meetings, which will be codified in the written minutes of the first
                        Neurology JRC meeting. Each Party will be responsible for the costs and expenses of its own employees or consultants attending Neurology JRC meetings. Ionis and Biogen will use reasonable efforts to schedule meetings of the
                        Neurology JRC to take place at the same location and on the same dates as meetings of the CSC and the joint development and steering committees under the Ionis/Biogen Additional Agreements, to maximize the use of each Party&#8217;s time,
                        increase information sharing efficiencies and reduce the cost of additional travel, lodging and related expenses.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">34</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="z30edf6bc856643fcb71ab3a520bc534a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Role of the Neurology JRC</u></font>. Without limiting any of the foregoing,
                        subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.4</u></font>, the Neurology JRC will perform the following functions, some or all of which may be addressed directly at any given Neurology
                        JRC meeting:</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zb26809f076604dc0a0ade12f72b85c98" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">maintain the list of High Interest Targets, ALS Targets, Collaboration Targets, and Biogen Alternate Modality Targets, as such lists may be updated from time to time in
                        accordance with this Agreement, and attach such lists to the minutes of the meeting of the Neurology JRC where any update to the High Interest Target List, ALS Target List or Collaboration Targets, Biogen Alternate Modality Targets
                        occurred;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z77faa96e2a9a4b91998ba7da0d63c1fb" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2.3(c)</u></font>, determine the number of High Interest Targets for which
                        activities to support Target Sanction will be conducted during each year of the Research Term;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z181600801c3749f195ef336adc30d3ef" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">review and approve amendments to the Core Research Plan and the Neurological Disease Research Plan (including any amendments thereto that terminate all activities under
                        such plans) as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections 1.2.2 </u></font>and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>1.2.3</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zb9377fc3a17a44a2a551ffe495c16695" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iv)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">allocate resources under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.11;</u></font></font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z6f248fed452f4bc79c342bb60d095ddf" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(v)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">determine the number of FTEs Ionis will use to perform drug discovery activities on ALS Targets;</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z44740af5f73e4e3f9dead56ccfc69eff" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(vi)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">as contemplated under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.6.1</u></font>, determine whether to re-allocate resources on
                        additional Collaboration Programs;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z4fe08764f0ba4d01875859346fcfd5d9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(vii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">during years [***] through [***] after the Effective Date, determine the appropriate allocation of Ionis&#8217; resources to the Core Research Plan, the Neurological Disease
                        Research Plan and each ASO Development Candidate Identification Plan, as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.11</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">35</font></div>
          <div id="DSPFPageBreak" style="page-break-after:always;">
            <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z20cf92195c8b4237b763674adfcd38c2" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(viii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">review the overall progress of Ionis&#8217; efforts to achieve Target Sanction with respect to each High Interest Target that has not achieved Target Sanction status;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z6556b81a35234be6ab3420c5a213ecc9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ix)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.3</u></font>, review each Target Sanction Data Package and determine the
                        best therapeutic modality to pursue for a High Interest Target;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="za98d05046f0c4a8b9315289358bd2f70" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(x)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.4</u></font>, review each Target Sanction Data Package for an Ionis
                        Neurology Target;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zc7b2a56e29374781853d17e62e18bbbc" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(xi)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">establish an ASO Development Candidate Identification Plan for each Collaboration Program as described in <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 1.10.1(a)</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z1201bed2fd7040c9a5efe1c6f295888b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(xii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">agree on any biomarker work to be performed in the ASO Development Candidate Identification Plan, and [***] is responsible for performing such biomarker work [***];</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z23dfbc27e950487e90b7cf6980fa3e46" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(xiii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(c)</u></font> and <font style="font-size: 10pt; font-family: 'Times
                          New Roman';"><u>Section 1.10.2(d)</u></font>, agree upon a high level pre-clinical toxicology strategy and Initial Development Plan for each Development Candidate;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z48dad4f199274daca90e1d02ac2b458f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(xiv)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">review the overall progress of Ionis&#8217; efforts to discover, identify, optimize and select the Development Candidate for each Collaboration Program;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z94ee9e300f834b669adda91e2ac3ece5" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(xv)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">monitoring progress of each Collaboration Program and maintaining a calendar of anticipated milestone achievement dates for each Collaboration Program;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z2c75aa18453b42ff80b555f840d65094" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(xvi)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">establishing teams and committees to oversee and manage activities under the Core Research Program, Neurological Disease Research Program and each Collaboration Program
                        up to Development Candidate designation as it deems necessary;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z8a2d4a9aa4094a4aa8cda2d56fe596af" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(xvii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">discuss upcoming academic and non-profit collaborations that a Party is negotiating or considering entering into; and</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">36</font></div>
          <div id="DSPFPageBreak" style="page-break-after:always;">
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        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z176d536a9056447d836edce191b42abf" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(xviii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">such other review and advisory responsibilities as may be assigned to the Neurology JRC by the CSC pursuant to this Agreement.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zb372b43b047a4503b569877df3c83a4d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.18.3.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Joint Development Committees</u></font>. For each Development Candidate, the CSC
                        will appoint a joint development committee (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurology</font>&#160;<font style="font-size: 10pt; font-family: 'Times New
                          Roman'; font-weight: bold; font-style: italic;">JDC</font>&#8221;) approximately [***] days prior to the date Ionis expects to designate a Development Candidate, to govern the activities under this Agreement with respect to such
                        Collaboration Program. Each Neurology JDC will report to the CSC and will consist of an equal number of representatives appointed by Ionis and Biogen. Each Neurology JDC member will be a senior clinical development leader or have
                        other experience and expertise appropriate for the stage of development of the Collaboration Program in the applicable disease area, and at least one of each Party&#8217;s members will have operational responsibility for the applicable
                        Collaboration Program. Each Party will designate one of its representatives who is empowered by such Party to make decisions related to the performance of such Party&#8217;s obligations under this Agreement to act as the co-chair of the
                        Neurology JDC. The co-chairs will be responsible for overseeing the activities of the Neurology JDC consistent with the responsibilities set forth below in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                            1.18.3</u></font>. <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 1.18.3</u></font> sets forth
                        certain Neurology JDC governance matters agreed to as of the Effective Date. Each Neurology JDC will determine its operating procedures at its first meeting, including the Neurology JDC&#8217;s policies for replacement of Neurology JDC
                        members, policies for participation by additional representatives or consultants invited to attend Neurology JDC meetings, and the location of meetings, which will be codified in the written minutes of the first Neurology JDC
                        meeting. Each Party will be responsible for the costs and expenses of its own employees or consultants attending Neurology JDC meetings. If practical, Ionis and Biogen will use reasonable efforts to schedule meetings of each
                        Neurology JDC to take place at the same location and on the same dates as meetings of the CSC and the joint development and steering committees under the Ionis/Biogen Additional Agreements, to maximize the use of each Party&#8217;s time,
                        increase information sharing efficiencies and reduce the cost of additional travel, lodging and related expenses.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z8fd14e5966e3468ba834282a19534681" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Role of the Neurology JDCs</u></font>. Without limiting any of the foregoing,
                        subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.4</u></font>, each Neurology JDC will perform the following functions, some or all of which may be addressed directly at any given Neurology
                        JDC meeting:</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zc672c7f4d40c411f9e3e2c5d989d52fe" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">establish the Initial Development Plan for each Development Candidate and update such plan as needed as provided in <font style="font-size: 10pt; font-family: 'Times
                          New Roman';"><u>Section 1.10.2(d)</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">37</font></div>
          <div id="DSPFPageBreak" style="page-break-after:always;">
            <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z1fc71deb011141b781284c94daba0eca" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">agree on Cost Estimates and the [***] milestone payments under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z7167ee3aeafe452e84a537c2bbef96da" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">approve Biogen-Approved Costs pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zbf97e5006bfc49a7a6922659f93ba338" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iv)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">if the milestone payment agreed upon in writing by the Parties pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>
                        with respect to a [***] exceeds $[***], establishing whether and how such payment shall be apportioned into smaller milestone payments as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                            1.10.2(e)</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z01b05e144d9f4682bbd921b4aa67d3f1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(v)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">if any Biogen-Approved Costs that result from [***] exceed $[***], establishing whether and how such payments shall be apportioned into smaller milestone payments as
                        described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1(a)</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zc776234b4b67462f97a1d002d85ec93a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(vi)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">establish a high-level preclinical toxicology strategy for each Collaboration Program under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                            1.10.2(c)</u></font>;</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zae090042632f416b987f7a1ed61ca9eb" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(vii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">establishing teams and committees to oversee and manage activities under each Collaboration Program after Development Candidate designation as it deems necessary; and</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z2fe6b2367d8f4783b26a5e6300a68ab1" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(viii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">such other review and advisory responsibilities as may be assigned to the Neurology JDC by the CSC pursuant to this Agreement.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z4d03392a89be4d5c920e1211d4885618" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.18.4.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Decision Making</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z3e46e72f8aa24962b2288922c5ad564c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Committee Decision Making</u></font><font style="font-size: 10pt; font-family:
                          'Times New Roman'; font-weight: bold;">. </font>Decisions by each of the CSC, Neurology JRC and Neurology JDC will be made by unanimous consent with each Party&#8217;s representatives having, collectively, one vote.&#160; At any given
                        meeting of any such committee, quorum will have deemed to be reached if a voting representative of each Party is present or participating in such meeting.&#160; No action taken at any meeting of any such committee will be effective
                        unless there is a quorum at such meeting. Unless otherwise specified in this Agreement, no action will be taken with respect to a matter for which the CSC, Neurology JRC or Neurology JDC, as applicable, has not reached unanimous
                        consensus.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">38</font></div>
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        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z0e60c998b11e43ae9b291b60c9c0fb0b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Implementation</u></font><font style="font-size: 10pt; font-family: 'Times New
                          Roman'; font-weight: bold;">.</font> Each Party will give due consideration to, and consider in good faith, the recommendations and advice of the CSC, the Neurology JRC and Neurology JDC (as applicable) regarding the conduct of
                        the Core Research Program, Neurological Disease Research Program and each Collaboration Program. Subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1</u></font> and <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 1.10.2</u></font>, prior to the License Effective Date with respect to the applicable Collaboration Program, (i) Ionis will have the final decision-making authority regarding [***]
                        and (ii) Biogen will have the final decision-making authority regarding [***]. After the License Effective Date with respect to a particular Collaboration Program, Biogen will have sole decision-making authority regarding [***] of
                        Collaboration Products for such Collaboration Program, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however, </font>that [***]. Except as otherwise expressly stated in this
                        Agreement, the CSC, the Neurology JRC and Neurology JDC will have no decision making authority and will act as a forum for sharing information about the activities conducted by the Parties hereunder and as an advisory body, in each
                        case only on the matters described in, and to the extent set forth in, this Agreement.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z85a5c30c10ca414d941280866d764d3c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.18.5.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis Obligation to Participate in the Neurology JRC, Neurology JDC and CSC</u></font>.
                        Ionis&#8217; obligation to participate in (i) the Neurology JRC, will terminate at the end of the ASO Development Candidate Identification Term, (ii) the Neurology JDC, will terminate upon Biogen&#8217;s exercise (or expiration) of the Option
                        for the last Collaboration Program, and (iii) the CSC, will terminate upon Biogen&#8217;s exercise (or expiration) of the Option for the last Collaboration Program. Thereafter, for each such governing body, Ionis will have the right, but
                        not the obligation, to participate in such meetings upon Ionis&#8217; request.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z23f3ca05d26e4cf4a69b95e1091e872e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.18.6.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Alliance Managers</u></font>. Each Party will appoint a representative to act as
                        its alliance manager under this Agreement (each, an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Alliance Manager</font>&#8221;). Each Alliance Manager will be responsible for
                        supporting the CSC, the Neurology JRC and Neurology JDC, and performing the activities listed in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u> 1.18.6</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">39</font></div>
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        </div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 2.</font></div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">EXCLUSIVITY COVENANTS</font></div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z830135191dd942a7b54b48decd3e4e70" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Exclusivity; Right of First Negotiation</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zabaa145588924db6a16efd47083934ff" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.1.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Exclusivity Covenants</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z48f47544fc674141adcd5eab1226749a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>The Parties&#8217; Exclusivity Covenants During the Research Term for High Interest
                            Targets</u></font>. Each Party agrees that, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">except</font> in the performance of its obligations or exercise of its rights under this Agreement
                        and except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.4</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.3</u></font> or <font style="font-size: 10pt; font-family: 'Times
                          New Roman';"><u>Section 10.4.4</u></font>, or as contemplated by any Neurology Plan, neither it nor any of its Affiliates will work independently or for or with any Third Party (including the grant of any license to any Third
                        Party) with respect to the discovery, research, development, manufacture or commercialization in the Field of an Oligonucleotide that is designed to bind to the RNA that encodes a High Interest Target from the Effective Date until
                        the earlier to occur of (i) the date such target is removed from the High Interest Target List, by Biogen or ceases to be a High Interest Target by operation of this Agreement, or (ii) the date on which the High Interest Target List
                        is dissolved in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.9</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z591297e9b37c4116b699eb614046516e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Exclusivity Covenants </u></font><font style="font-size: 10pt; font-family:
                          'Times New Roman'; font-weight: bold;"><u>during the Research Term for Ionis Neurology Targets</u></font>. Ionis agrees that neither it nor any of its Affiliates will work for the benefit of any Third Party (including the grant of
                        any license to any Third Party that would diminish Biogen&#8217;s rights under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.4</u></font> or prevent Ionis from granting Biogen a license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font>) with respect to the discovery, research, development, manufacture or commercialization in the Field of an Oligonucleotide that is designed to
                        bind to the RNA that encodes an Ionis Neurology Target from the Effective Date until the earlier to occur of (i) the date such target ceases to be a Neurology Target by operation of this Agreement, or (ii) the expiration of the
                        Research Term.</font></div>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">40</font></div>
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        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z18a7980047c14982819806d8f82446dc" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Exclusivity Covenants for Biogen Alternate Modality Targets</u></font>. With
                        respect to each Biogen Alternate Modality Target, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">except</font> in the performance of its obligations or exercise of its rights under this Agreement
                        and except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.3</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.4</u></font>, neither Ionis nor any of its Affiliates will work independently or for or with any Third Party (including the grant of any license to any Third
                        Party) with respect to the discovery, research, development, manufacture or commercialization of an Oligonucleotide designed to bind to the RNA encoding such Biogen Alternate Modality Target without Biogen&#8217;s prior written consent; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that if (A) Biogen, its Affiliates or Sublicensees have not [***] within [***] (or, if Biogen has used Commercially Reasonable
                        Efforts to [***], within [***]) after the date the applicable Neurology Target becomes a Biogen Alternate Modality Target in accordance with this Agreement, or (B) after [***], Biogen, its Affiliates and Sublicensees thereafter
                        cease to use Commercially Reasonable Efforts to develop or commercialize such Product (or otherwise stops developing or commercializing such Product), then (i) the exclusive license granted to Biogen under <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> for such Biogen Alternate Modality Target will convert to a non-exclusive license, and (ii) Ionis and its Affiliates may independently or for or with any Third
                        Party (including the grant of any license to any Third Party) research, develop, and commercialize Oligonucleotides designed to bind to the RNA encoding such Biogen Alternate Modality Target (each such Oligonucleotide, an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Non-Exclusive Product</font>&#8221;), but not, for the avoidance of doubt, any molecule or product designed to [***] that is not
                        [***], and the license to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> will become a non-exclusive license to the extent necessary to allow Ionis to conduct such
                        activities.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zfcd850a1626143d5b7acb334a668a62f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>The Parties&#8217; Exclusivity Covenants </u></font><font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-weight: bold;"><u>during the Option Period for Collaboration Targets</u></font>. Each Party agrees that, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">except</font>
                        in the performance of its obligations or exercise of its rights under this Agreement and except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.2</u></font>, <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 2.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.3</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                            10.4.4</u></font>, neither it nor any of its Affiliates will work independently or for or with any Third Party (including the grant of any license to any Third Party) with respect to discovery, research, development, manufacture
                        or commercialization in the Field of an Oligonucleotide that is designed to bind to the RNA that encodes a Collaboration Target from the date such gene target was designated a Collaboration Target under this Agreement through the
                        expiration or earlier termination of the applicable Option Period.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z587906c81d6b401eadebb482f914a118" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>The Parties&#8217; Exclusivity Covenants </u></font><font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-weight: bold;"><u>after the License Effective Date</u></font>. <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Except</font> in the performance of its
                        obligations or exercise of its rights under this Agreement and except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.2</u></font>, <font style="font-size: 10pt; font-family: 'Times
                          New Roman';"><u>Section 2.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.3</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.4</u></font>,
                        if Biogen timely exercises an Option in accordance with this Agreement, then neither Ionis nor Biogen nor their respective Affiliates will work independently or for or with any Third Party (including the grant of any license to any
                        Third Party) with respect to:</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">41</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="z6f4758fac66e4bdb888e72565446e810" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 27pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">discovery, research or development in the Field of an Oligonucleotide that is designed to bind to the RNA that encodes the applicable Collaboration Target related to
                        such Option until [***]; and</font></div>
                  </td>
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            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z716f08fba1d64ffa8060a2051fa2bd19" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 117pt;"><br>
                  </td>
                  <td style="width: 27pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">on a country-by-country basis, commercializing in the Field an Oligonucleotide that is designed to bind to the RNA that encodes such Collaboration Target until [***].</font></div>
                  </td>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z269d489e794f43e7bf1ceca77530a2c6" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Failure to Defer or Designate a High Interest Target a Collaboration Target or
                            Biogen Alternate Modality Target</u></font>. If, after a High Interest Target achieves Target Sanction, Biogen (i) fails to timely designate such High Interest Target as a Collaboration Target or a Biogen Alternate Modality
                        Target (or, if applicable elect to defer under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.3</u></font>) on the applicable timelines set forth in <font style="font-size: 10pt; font-family: 'Times
                          New Roman';"><u>Section 1.3</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8</u></font>, (ii) fails to timely pay the applicable milestone payment under <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 6.2.1</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.2</u></font>, (iii) under <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 10.2.1</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.2</u></font> voluntarily terminates its license under <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 4.1.1(b)</u></font> with respect to a High Interest Target Biogen designated as a Biogen Alternate Modality Target, or (iv) notifies Ionis that it has terminated an ALS Collaboration Program after the
                        Initiation of a Phase 1 Trial for such program or fails to timely pay a milestone payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.5</u></font> with respect to a particular ALS Collaboration
                        Program, then in each case for a period of [***] after the date of such failure or such termination, as applicable, (A) neither Biogen nor its Affiliates will independently or for or with any Third Party (including the grant of any
                        license to any Third Party) discover, research, develop, manufacture or commercialize an Oligonucleotide designed to bind to the RNA encoding such High Interest Target and (B) if Biogen or any of its Affiliates or licensees
                        discovers, researches, develops, manufactures or commercializes a Biogen Alternate Modality Product for such High Interest Target and such High Interest Target is not a Pre-Existing Target, then (1) the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font> will apply with respect to such Biogen Alternate Modality Product, (2) Biogen will pay Ionis all amounts owed (or which would have been owed absent
                        such original failure or such termination) under such <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font> with respect to such Biogen Alternate Modality Product (to the extent such amounts have
                        not previously been paid with respect to the applicable Biogen Alternate Modality Target) in accordance with the terms hereof, (3) to the extent Ionis has the ability to do so, Ionis will grant Biogen the license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> with respect to such Biogen Alternate Modality Target, and (4) <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                            2.1.1(c)</u></font> will not apply with respect to such Biogen Alternate Modality Product.&#160; For the avoidance of doubt, nothing in this Agreement shall restrict Biogen&#8217;s or its Affiliate&#8217;s or licensee&#8217;s discovery, research,
                        development, manufacture, or commercialization of a product for a Pre-Existing Target that is not an Oligonucleotide designed to bind to the RNA that encodes such Pre-Existing Target.</font></div>
                  </td>
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            </table>
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        <div><br>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">42</font></div>
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            <table cellspacing="0" cellpadding="0" id="zc032f25d2d9a4ef9b0dcba3737ad793b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.1.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Limitations and Exceptions to Ionis&#8217; Exclusivity Covenants</u></font>.<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>Notwithstanding anything to the contrary in this Agreement, Ionis&#8217; practice of the following will not violate <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 2.1.1</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2</u></font> or clause (d) of <font style="font-size: 10pt; font-family: 'Times New
                          Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>:</font></div>
                  </td>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z32ff7c86833e4a80a2f404cb27d54bc2" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The discovery, research, development, manufacture or commercialization of Gene-Editing Products or messenger RNA solely to the extent agreed by the Parties in writing;</font></div>
                  </td>
                </tr>

            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zd8e668f24ffb44f8bd370aec17639750" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Any activities pursuant to the Prior Agreements as in effect on the Effective Date;</font></div>
                  </td>
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        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zb982a9c58c63436da7ba337d47bb81c9" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The granting of, or performance of obligations under, Permitted Licenses;</font></div>
                  </td>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="za18f087a8bdc445aaf1b6645254b6b9c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The research, development or commercialization of an Ionis Multi-Indication Compound to the extent permitted under <font style="font-size: 10pt; font-family: 'Times
                          New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>;</font></div>
                  </td>
                </tr>

            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z372c0e3e5b5a4b2daa962c02600fff3a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The exercise of its rights under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.2</u></font>;</font></div>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z492ce8502b52439796e0ef474eb50c7a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The discovery, research, development, manufacture or commercialization of a Pre-Existing Competitive Collaboration Product in accordance with <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>12.5.2(b)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>12.6</u></font>; and</font></div>
                  </td>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zf0395ad72ef74dd2bdc8445d2a8ceaaf" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(g)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The limited continuation of discovery, research, development, manufacture or commercialization of Acquired Competitive Product(s) as permitted under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.3(a)</u></font>&#160;and in accordance with <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.3(a)</u></font>&#160;and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.6</u></font>.</font></div>
                  </td>
                </tr>

            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z3299c20f96134629a935c97a38df395a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.1.3.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Limitations and Exceptions to Biogen&#8217;s Exclusivity Covenants</u></font>.
                        Notwithstanding anything to the contrary in this Agreement, Biogen&#8217;s or its Affiliates&#8217; practice of the following will not violate <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 2.1.1</u></font>&#160;or clause (b) of <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>:</font></div>
                  </td>
                </tr>

            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zddabc90b625f43c3b4e4e7c853796cdb" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The discovery, research, development, manufacture or commercialization of Gene-Editing Products or messenger RNA solely to the extent agreed by the Parties in writing;</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">43</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="z4322dfc5e0684dfe9e01bdb70e32a1c4" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the discovery, research, development, manufacture or commercialization of a Pre-Existing Competitive Collaboration Product in accordance with <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 12.5.2(b)</u></font>&#160;and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>
                            12.6</u></font>; or</font></div>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zc235bf575072482c89f3546086853c30" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 81pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the limited continuation of discovery, research, development, manufacture or commercialization of Acquired Competitive Product(s) as permitted under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.3(a)</u></font>&#160;and in accordance with <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>12.5.3(a)</u></font>&#160;and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.6</u></font>.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zcb64468283454e89b670eca667b4437e" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt;"><br>
                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.1.4.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Effect of Exclusivity on Indications</u></font>. The Compounds are designed to bind
                        to the RNA that encodes a Collaboration Target with the intent of treating a Neurological Disease in the Field. Ionis and Biogen are subject to exclusivity obligations under <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 2.1</u></font>; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">however</font>, the Parties acknowledge and agree that, except as otherwise provided herein, each Party and
                        its Affiliates (on its own or with a Third Party) may continue to discover, research, develop, manufacture and commercialize products that are designed to bind to the RNA that encodes a gene that is <font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-style: italic;"><u>not</u></font> (i) a High Interest Target to the extent <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(a)</u></font> still applies, (ii) a
                        Biogen Alternate Modality Target to the extent <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(c)</u></font> still applies, or (iii) a Collaboration Target, in each case for any indication, even if
                        such products are designed to treat a Neurological Disease.</font></div>
                  </td>
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            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z813543624265496d9e9d9a6a658a14f8" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

                <tr>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Right of First Negotiation for Follow-On Compounds</u></font>. On a Collaboration
                        Program-by-Collaboration Program basis, during the period commencing on the Effective Date and ending upon (i) if the applicable Option is not exercised in accordance with this Agreement, [***], or (ii) if the applicable Option is
                        exercised in accordance with this Agreement, [***] (such period, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">ROFN Period</font>&#8221;), Ionis hereby grants to Biogen a right
                        of first negotiation to develop and commercialize any Follow-On Compound developed by or on behalf of Ionis, which right of first negotiation is granted on the following terms and conditions:</font></div>
                  </td>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z8e54d0708e9444e690fa792ff035ae73" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.2.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Within [***], Biogen may provide Ionis with a non-binding, good faith written notice expressing Biogen&#8217;s desire for Ionis to identify a Follow-On Compound (a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Follow-On Interest Notice</font>&#8221;). If (i) Biogen does not, within such [***] period, provide Ionis with a Follow-On Interest Notice,
                        or (ii) Biogen does timely provide Ionis with a Follow-On Interest Notice but the Parties do not agree on a [***] related to such Follow-On Compound by 5:00 pm (Eastern Time) on the [***] following the date of the License Effective
                        Date with respect to such Collaboration Program, then, Ionis may work independently or with any of its Affiliates or any Third Party with respect to the discovery, research, development and manufacture of a Follow-On Compound; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that during the ROFN Period, Ionis will not grant any license (or an option to obtain such a license) under any intellectual
                        property owned, controlled or licensed by Ionis to make, use or sell any Follow-On Compound (a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Follow-On Agreement</font>&#8221;) <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>unless and until</u></font> Ionis provides a written notice to Biogen (a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight:
                          bold; font-style: italic;">Follow-On Negotiation Notice</font>&#8221;), which notice identifies [***].&#160; Ionis will not initiate negotiations regarding or enter into such a Follow-On Agreement with any Third Party until [***].</font></div>
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            <table cellspacing="0" cellpadding="0" id="zdc1fd78c0ac14d2d96e692e98266768b" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.2.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Biogen or one of its Affiliates responds within [***] after its receipt of the Follow-On Negotiation Notice indicating that Biogen or one of its Affiliates desires
                        to negotiate with Ionis regarding the proposed Follow-On Agreement, Ionis and Biogen or one of its Affiliates will negotiate in good faith with each other until the [***] after the date Ionis provided Biogen the Follow-On
                        Negotiation Notice (or such other period as mutually agreed by the Parties) (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Negotiation Period</font>&#8221;) regarding a mutually
                        satisfactory Follow-On Agreement (which may take the form of an amendment to this Agreement). During the Negotiation Period, Ionis will make at least [***] to Biogen or its Affiliate setting forth all material business and legal
                        terms on which Ionis would be willing to enter into the proposed Follow-On Agreement with Ionis; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, that</font> neither Party will have any
                        obligation to enter into a Follow-On Agreement. If the Negotiation Period expires before Biogen or its Affiliate and Ionis have entered into such a Follow-On Agreement, Ionis will have no further obligation to negotiate with Biogen
                        or its Affiliates with respect to such Follow-On Agreement and Ionis will be free to negotiate and enter an agreement with a Third Party with respect to a Follow-On Agreement [***]; <font style="font-size: 10pt; font-family: 'Times
                          New Roman'; font-style: italic;">provided, however</font>, that Ionis will not enter into any such Follow-On Agreement with any Third Party unless the terms and pricing of such Follow-On Agreement, [***] during the Negotiation
                        Period. If, with respect to any Follow-On Compound that was the subject of the Follow-On Agreement previously discussed by the Parties, after the end of the Negotiation Period and prior to Ionis entering into a Follow-On Agreement
                        with a Third Party, [***] regarding the Follow-On Compound, Ionis&#8217; obligations and Biogen&#8217;s rights under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2.1</u></font> and this <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 2.2.2</u></font> will reset and Ionis will provide Biogen with a new Follow-On Negotiation Notice.</font></div>
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        </div>
        <div><br>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="za963e35e91d647f5b031e12e83864997" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.2.3.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Any Follow-On Agreement entered into by Ionis with a Third Party in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2.2</u></font>
                        will be a Permitted License to the extent related to the Follow-On Compound.</font></div>
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            </table>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z7fea33142f4d4355adc8d2451430c961" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.2.4.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Notwithstanding anything to the contrary in this Agreement, until [***], Ionis will provide to Biogen a Follow-On Negotiation Notice for each [***] pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">unless</font> Ionis enters into a Follow-On Agreement with a
                        Third Party pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2</u></font> and the terms of such agreement do not permit Ionis to grant Biogen rights with respect to the applicable
                        Follow-On Compound.</font></div>
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        <div><br>
        </div>
        <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Except as expressly set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2</u></font>, or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.4</u></font>, in no event will Ionis have the right to [***].</font></div>
        <div><br>
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        <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 3.</font></div>
        <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">EXCLUSIVE OPTION</font></div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zbaa8be61ee874a4caa5f41fcb792fd40" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Option</u></font>.</font></div>
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        <div><br>
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        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z18e59d30ae534a37b829616bd864acea" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Advance Data Disclosure</u></font>. On or about 90 days before the date on which
                        Ionis estimates that the database will be locked for the first PoC Trial for a particular Collaboration Program that is being conducted by Ionis (each an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight:
                          bold; font-style: italic;">Estimated Lock Date</font>&#8221;), Ionis will provide Biogen with a written notice of such Estimated Lock Date. If Biogen provides written notice to Ionis [***] after Biogen&#8217;s receipt of the notice regarding
                        the Estimated Lock Date that Biogen has a good faith intention to exercise the Option for the applicable Collaboration Program under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3</u></font>, then
                        as soon as reasonably practicable after Ionis receives such notice from Biogen, Ionis will provide Biogen with an early preview of the information to be included in the [***] for the applicable Collaboration Program to the extent
                        then in Ionis&#8217; possession and not already provided to Biogen, to assist Biogen with its decision of whether to exercise the Option. Within 15 Business Days after Biogen&#8217;s receipt of such data, Biogen will provide Ionis with a [***]
                        notice of whether Biogen still intends to exercise the Option for the applicable Collaboration Program, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Biogen&#8217;s
                        failure to do so will not be deemed a breach of this Agreement.</font></div>
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        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z5dfc1772a6564bbf9adb3a7bce9210ba" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>PoC Trial Completion Notice</u></font>. On a Collaboration Program-by-Collaboration
                        Program basis where Ionis conducts the first PoC Trial, Ionis will provide to Biogen or its designated Affiliate (i) a copy of the most recent Investigator&#8217;s Brochure for the applicable Collaboration Product, (ii) written notice
                        from Ionis regarding completion of the first PoC Trial, and (iii) the PoC Data Package for such Collaboration Program, to the extent not already provided to Biogen under <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 3.1.1</u></font> above (such notice and package, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">PoC Trial Completion Notice</font>&#8221;) promptly, and in
                        any event within [***] days after database lock for the PoC Trial for such Collaboration Program.&#160; Within 15 days of receipt of the PoC Trial Completion Notice, Biogen or an Affiliate will notify Ionis of any omissions or
                        deficiencies that Biogen or its Affiliate believes in good faith cause the PoC Trial Completion Notice to be incomplete (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Deficiency







                          Notice</font>&#8221;). Ionis will promptly, and in any event within 15 days of receipt of the Deficiency Notice, resubmit a complete PoC Trial Completion Notice to Biogen or its designated Affiliate, including any information required
                        to be included in the PoC Data Package that Biogen identified in the Deficiency Notice. If the Parties do not agree as to whether the PoC Trial Completion Notice is complete, the matter will be referred to the Executives for
                        resolution. The Executives will meet promptly and negotiate in good faith to resolve the dispute and agree upon a complete PoC Trial Completion Notice.</font></div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">46</font></div>
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            <table cellspacing="0" cellpadding="0" id="zad0519a32aa04f6096bbadf09d600419" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.3.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Option and Option Deadline</u></font>. On a Collaboration Program-by-Collaboration
                        Program basis, Ionis hereby grants to Biogen and its Affiliates an exclusive option to obtain the license set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> with respect to
                        such Collaboration Program (each an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option</font>&#8221;). Each Option for a Collaboration Program that is not an ALS Collaboration
                        Program or a Biogen Conducted Non-ALS Collaboration Program will be available to Biogen and its Affiliates until 5:00 pm (Eastern Time) on the [***] following Biogen&#8217;s receipt of a complete PoC Trial Completion Notice for the
                        applicable Collaboration Program (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Standard</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight:
                          bold; font-style: italic;">Option Deadline</font>&#8221;). Each Option for an ALS Collaboration Program will be available to Biogen and its Affiliates until 5:00 pm (Eastern Time) on the earlier of (A) the [***] following Biogen&#8217;s
                        receipt of the data generated under the statistical analysis plan after initial database lock for the first PoC Trial for the applicable ALS Collaboration Program, and (B) the [***] of the date a Development Candidate under such ALS
                        Collaboration Program was designated (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">ALS</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight:
                          bold; font-style: italic;">Option Deadline</font>&#8221;). Each Option for a Biogen Conducted Non-ALS Collaboration Program will be available to Biogen and its Affiliates until 5:00 pm (Eastern Time) on the earlier of (X) the [***]
                        following Biogen&#8217;s receipt of the data generated under the statistical analysis plan after initial database lock for the first PoC Trial for the applicable Biogen Conducted Non-ALS Collaboration Program, and (Y) the [***] of the
                        date a Development Candidate under such Biogen Conducted Non-ALS Collaboration Program was designated (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Conducted
                          Non-ALS</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Deadline</font>&#8221;). Notwithstanding the foregoing, if Biogen determines that an HSR Filing is required to
                        be made under the HSR Act to exercise an Option and notifies Ionis of such determination within [***] after Biogen&#8217;s receipt of the complete PoC Trial Completion Notice, the Parties will promptly file an HSR Filing in accordance
                        with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.4</u></font> and the Option Deadline will be extended until 5:00 pm (Eastern Time) on the fifth Business Day after the HSR Clearance Date. If, by
                        the Option Deadline, Biogen or its designated Affiliate (i) notifies Ionis in writing that it wishes to exercise the applicable Option, and (ii) pays to Ionis the license fee set forth in <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 6.6</u></font>, Ionis will, and hereby does, grant to Biogen or its designated Affiliate the license set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font>.
                        If, by the Option Deadline, Biogen or its designated Affiliate has not both (y) provided Ionis a written notice stating that Biogen is exercising its Option, and (z) paid Ionis the license fee in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.6</u></font>, then Biogen&#8217;s Option for the applicable Collaboration Program will expire and Biogen will promptly transfer to Ionis all data, results and
                        information (including Biogen&#8217;s Confidential Information and any regulatory documentation (including drafts)) related to the testing and Clinical Studies under such Collaboration Program in the possession of Biogen and its
                        contractors to the extent such data, results and information were generated by or on behalf of Biogen under this Agreement (and [***] will pay all out-of-pocket direct Third Party costs and expenses in transferring such data,
                        results and information together with Biogen&#8217;s FTE Cost in transferring such data, results and information).</font></div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">47</font></div>
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            <table cellspacing="0" cellpadding="0" id="z45ec44b367774949bf0af178201d38d3" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1.4.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>HSR Compliance</u></font>.</font></div>
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        <div style="text-align: justify;">
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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div style="text-indent: 9pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><u>HSR Filing</u></font>. If Biogen
                        notifies Ionis pursuant to <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 1.7</u></font> or <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 3.1.3</u></font>
                        that an HSR Filing is required for Biogen to receive the license under <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 4.1.1(b)</u></font> or exercise an Option under this Agreement, each of
                        Biogen and Ionis will, within five Business Days after such notice from Biogen (or such later time as may be agreed to in writing by the Parties), file with the United States Federal Trade Commission (&#8220;<font style="font-size: 10pt;
                          font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">FTC</font>&#8221;) and the Antitrust Division of the United States Department of Justice (&#8220;<font style="font-size: 10pt; font-family: &quot;Times New
                          Roman&quot;; font-weight: bold; font-style: italic;">DOJ</font>&#8221;), any HSR Filing required with respect to the transactions contemplated hereby. The Parties will cooperate with one another to the extent necessary in the
                        preparation of any such HSR Filing. Each Party will be responsible for its own costs and expenses (other than filing fees, which Biogen will pay) associated with any HSR Filing.</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="z732629e26beb4fbabd0b005154de48a8" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div style="text-indent: 9pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><u>HSR Clearance</u></font>. In
                        furtherance of obtaining HSR Clearance for an HSR Filing filed under <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 3.1.4(a)</u></font>, Ionis and Biogen will use their respective commercially
                        reasonable efforts to resolve as promptly as practicable any objections that may be asserted with respect to this Agreement or the transactions contemplated by this Agreement under any antitrust, competition or trade regulatory law.
                        In connection with obtaining such HSR Clearance from the FTC, the DOJ or any other governmental authority, Biogen and its Affiliates will not be required to (i) sell, divest (including through a license or a reversion of licensed or
                        assigned rights), hold separate, transfer or dispose of any assets, operations, rights, product lines, businesses or interest therein of Biogen or any of its Affiliates (or consent to any of the foregoing actions); or (ii) litigate
                        or otherwise formally oppose any determination (whether judicial or administrative in nature) by a governmental authority seeking to impose any of the restrictions referenced in clause (i) above.</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="z7f22978c61c7458c919d61bd32cee8e8" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Changing or Adding Modalities</u></font>.</font></div>
                  </td>
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            </table>
          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="zb6a05f164bdb435c9bc35352b41e4cf0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2.1.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Changing to a Collaboration Target</u></font>. Provided that Biogen has complied
                        with its diligence obligations under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(c)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1.2</u></font>, at
                        any time during the Research Term after Biogen has made the applicable payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.2</u></font> with respect to a Biogen Alternate Modality Product,
                        subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.3(a)</u></font>, Biogen may elect to change such Biogen Alternate Modality Target to a Collaboration Target upon written notice to Ionis.
                        Thereafter, (i) Biogen will pay Ionis the milestone payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.1</u></font> (as such payment may be modified pursuant to <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 3.2.3(a)</u></font>), such payment to be made within [***] days after Biogen&#8217;s notice under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.1</u></font>,
                        (ii) Ionis will prepare and submit to the Neurology JRC an ASO Development Candidate Identification Plan for such Collaboration Target within [***] days after receipt of Biogen&#8217;s notice pursuant to this <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>Section 3.2.1</u></font>, which plan will be agreed upon as provided in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1(a)</u></font>, (iii) the Parties
                        will seek to discover and develop a Development Candidate for such target pursuant to such plan and the provisions of this Agreement and (iv) such target will no longer be a Biogen Alternate Modality Target hereunder.</font></div>
                  </td>
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        <div><br>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">48</font></div>
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            <table cellspacing="0" cellpadding="0" id="z51951c937f6247508e7e5ad277e35b23" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2.2.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Changing to a Biogen Alternate Modality Target</u></font>.<font style="font-size:
                          10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160; </font>At any time during the Term after Biogen has made the applicable payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.1</u></font>
                        for a Collaboration Program, Biogen may elect to change the applicable Collaboration Target under such Collaboration Program to a Biogen Alternate Modality Target upon written notice to Ionis, in which case the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.3(b)</u></font> will apply, and as of the date of such notice, Ionis will be deemed to have granted Biogen the license under <font style="font-size: 10pt;
                          font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> with respect to such target and such target will no longer be a Collaboration Target hereunder; <font style="font-size: 10pt; font-family: 'Times New Roman';
                          font-style: italic;">provided, however</font>, that Biogen will not have the right to change a Collaboration Target to a Biogen Alternate Modality Target if such Collaboration Target is a Pre-Existing Target.&#160; Within [***] days of
                        the later of (a) Ionis&#8217; receipt of Biogen&#8217;s notice electing to change a particular Collaboration Target to a Biogen Alternate Modality Target, and (b) Ionis&#8217; receipt of the data generated under the statistical analysis plan after
                        initial database lock for any ongoing Clinical Study under the applicable Collaboration Program, by written notice to Biogen, Ionis may elect to either (i) cease all development activities under this Agreement relating to any ASO
                        designed to bind to the applicable Biogen Alternate Modality Target (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font>, the former Collaboration Target), until otherwise permitted to conduct such
                        development activities under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(c)</u></font>, or (ii) subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.3(b)</u></font>,
                        continue to develop and commercialize on its own or with a Third Party such ASOs (or any other Oligonucleotides) designed to bind to the applicable Biogen Alternate Modality Target (<font style="font-size: 10pt; font-family: 'Times
                          New Roman';"><u>i.e.</u></font>, the former Collaboration Target).&#160; If Ionis makes an election under clause (ii) of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.2</u></font>, then <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.3(d)</u></font> will apply to such former Collaboration Target.</font></div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">49</font></div>
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          <div>
            <table cellspacing="0" cellpadding="0" id="zc55745f83a8f48e18ad81890006a9562" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2.3.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Economics for Changing Modalities</u></font>.</font></div>
                  </td>
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          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="za69b43e992284f7584c1ec61f69d037f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.1</u></font>, Biogen elects to change a Biogen Alternate Modality Target
                        to a Collaboration Target, the provisions related to Collaboration Programs under this Agreement, including to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections 6.2</u></font>, <font style="font-size:
                          10pt; font-family: 'Times New Roman';"><u>6.4</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.6</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.7</u></font>, and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.10</u></font> will apply with respect to such Collaboration Target, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided,
                          however</font>, that (i) if Biogen paid Ionis the milestone payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.2</u></font> with respect to such target prior to the date such target
                        changed to a Collaboration Target, then the milestone payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.1</u></font> with respect to such Collaboration Target will be reduced to $[***],
                        (ii) if Biogen paid Ionis a milestone payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.3</u></font> with respect to such target prior to the date such target changed to a Collaboration
                        Target, then Biogen may credit the amount of such payments against the amounts due Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections 6.6</u></font> and, to the extent applicable, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.7</u></font>.</font></div>
                  </td>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="ze0611fd5414245dc9ff2e785121c043c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.2</u></font>, Biogen elects to designate a Collaboration Target as a
                        Biogen Alternate Modality Target, the provisions related to Biogen Alternate Modality Programs under this Agreement, including <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections 6.3</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.9</u></font> will apply with respect to such Biogen Alternate Modality Target; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided,











                          however</font>, that (i) if the Collaboration Target Biogen changed to a Biogen Alternate Modality Target was not an ALS Target, then no payment will be due under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                            6.2.2</u></font> with respect to such Biogen Alternate Modality Target and (ii) if Ionis elects to continue to develop and commercialize such Oligonucleotides under clause (ii) of <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 3.2.2</u></font> Biogen will not be required to pay Ionis any un-accrued milestone payments or royalties under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.3</u></font>
                        and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.9</u></font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">solely</font> with respect to the applicable Biogen
                        Alternate Modality Product Developed and Commercialized by Biogen as a result of its conversion to a Biogen Alternate Modality Target under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.2</u></font>.</font></div>
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        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z7881cb5fef304a8482b85ca865425d62" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2.4.</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Adding an Additional Modality</u></font>.</font></div>
                  </td>
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          </div>
        </div>
        <div><br>
        </div>
        <div style="text-align: justify;">
          <div>
            <table cellspacing="0" cellpadding="0" id="z403f9836edcb48d0a33cd9fca91cbdda" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                  </td>
                  <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                  <td style="width: auto; vertical-align: top; text-align: justify;">
                    <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Adding a Collaboration Target</u></font>. Provided that Biogen has complied with
                        its diligence obligations under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(c)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1.2</u></font>, at any
                        time during the Research Term after Biogen has made the applicable payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.2</u></font> with respect to a Biogen Alternate Modality Target, Biogen
                        may elect to add such Biogen Alternate Modality Target as a Collaboration Target upon written notice to Ionis. Thereafter, (i) Biogen will pay Ionis the milestone payment under <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>Section 6.2.1</u></font>, such payment to be made within [***] days after Biogen&#8217;s notice under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.4(a)</u></font>, (ii) Ionis will
                        prepare and submit to the Neurology JRC an ASO Development Candidate Identification Plan for such Collaboration Target within [***] days after receipt of Biogen&#8217;s notice pursuant to this <font style="font-size: 10pt; font-family:
                          'Times New Roman';"><u>Section 3.2.4(a)</u></font>, which plan will be agreed upon as provided in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1(a)</u></font> and the Parties will seek to
                        discover and develop a Development Candidate for such target pursuant to such plan and the provisions of this Agreement (including, for the avoidance of doubt, the provisions of <font style="font-size: 10pt; font-family: 'Times New
                          Roman';"><u>ARTICLE 6</u></font>), (iii) <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(c)</u></font> will not apply with respect to any activities conducted by Ionis pursuant to a Neurology Plan
                        with respect to such target and (iv) Biogen may continue Developing, Manufacturing and Commercializing a Biogen Alternate Modality Product for the applicable Biogen Alternate Modality Target in accordance with the terms of this
                        Agreement (including, for the avoidance of doubt, the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font>).</font></div>
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            </div>
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          <div style="text-align: center;" id="DSPFPageNumberArea"><font style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;" id="DSPFPageNumber">50</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9640b92a6a844bb3a5da64517cc87538">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; font-family: &quot;Times New Roman&quot;; font-size: 10pt; font-weight: bold;">&#160;(b)</td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Adding a Biogen Alternate Modality Target</u></font>. At any time during the
                            Term after Biogen has made the applicable payment under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.1</u></font> for a Collaboration Program, Biogen may elect to add such Collaboration Target
                            as a Biogen Alternate Modality Target upon written notice to Ionis; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Biogen shall not have the right to add such
                            Collaboration Target as a Biogen Alternate Modality Target if such Collaboration Target is a Pre-Existing Target. Thereafter, (a) upon Biogen&#8217;s payment of the applicable milestone under <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 6.2.2</u></font>, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.5,</u></font> such payment to be made within [***] days after Biogen&#8217;s
                            notice under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.4(b)</u></font>, (i) Ionis will be deemed to have granted Biogen the license under <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 4.1.1(b)</u></font> with respect to such target and (ii) Biogen may Develop, Manufacture and Commercialize a Biogen Alternate Modality Product for the applicable Biogen Alternate Modality Target
                            in accordance with the terms of this Agreement (including, for the avoidance of doubt, the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font>) and (b) the Parties will continue
                            all activities under this Agreement with respect to the applicable Collaboration Program.</font></div>
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            <div><br>
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            <div style="text-align: justify;">
              <div>
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                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>HSR Compliance with Respect to Biogen Alternate Modality Targets</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">.&#160; </font>If Biogen determines that an HSR Filing is required to be made under the HSR Act for Biogen to receive the license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> with respect to any Biogen Alternate Modality Target that is designated under <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 3.2.2</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.4.2</u></font> and notifies Ionis of such determination within 10 days after Biogen&#8217;s notice to Ionis under
                            such section, the Parties will promptly file an HSR Filing in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.4</u></font> and the deadline for Biogen to pay Ionis the milestone
                            payment (or, if applicable, a portion thereof as provided in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.3)</u></font> under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                                6.2.2</u></font> will be extended until 5:00 pm (Eastern Time) on the fifth Business Day after the HSR Clearance Date.</font></div>
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            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">51</font></div>
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              <div>
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                    <div>
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                            <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2.6.</font></td>
                            <td style="width: auto; vertical-align: top; text-align: justify;">
                              <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Changes One-Time Only</u></font><font style="font-size: 10pt;
                                    font-family: 'Times New Roman'; font-weight: bold;">. </font>Once Biogen has elected to change a Collaboration Target to a Biogen Alternate Modality Target, or to change a Biogen Alternate Modality Target to a
                                  Collaboration Target under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.1</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.2</u></font>, as
                                  applicable, Biogen cannot exercise its rights under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2</u></font> to change such target back to a Collaboration Target or Biogen Alternate
                                  Modality Target, as applicable, or add such a Collaboration Target or Biogen Alternate Modality Target, as applicable, without Ionis&#8217; written consent.</font></div>
                            </td>
                          </tr>

                      </table>
                      <div> <br>
                      </div>
                    </div>
                  </div>
                </div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5228f976cfad4a75bca5bde0233fc2a3">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Restrictions on Ionis&#8217; Right to Grant Diagnostic Rights; Right to Negotiate
                                Diagnostic Rights</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z40cb6f770d55424c82a706548caca31b">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.3.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">On a Collaboration Product-by-Collaboration Product and Biogen Alternate Modality Product-by-Biogen Alternate Modality Product basis, Ionis hereby grants to Biogen
                            and its Affiliates an option (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Diagnostic Option</font>&#8221;) to negotiate during the Full Royalty Period or Biogen Alternate
                            Modality Royalty Period, as applicable, the terms of an agreement under which [***]. The Diagnostic Option will be available to Biogen and its Affiliates until the expiration of the [***] or [***], as applicable, for the
                            applicable Collaboration Product or Biogen Alternate Modality Product.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z64773917d0bc4c5d8bb19ecb9fd51022">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.3.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">During the [***] or [***], as applicable, Ionis (i) has the right to [***], and (ii) will not [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfc45c6e7a6544c5da5b9853ea001d6c1">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.3.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, during the [***] or [***], as applicable, Ionis grants any Third Party a [***], then Ionis will promptly notify Biogen of such [***] and will offer Biogen a
                            [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 4.</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">LICENSE GRANTS</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z717e0b5ba4f04bd2a5197d6772784c54">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>License Grants to Biogen</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z538b7e8e18d64512a6f828a721ffbddc">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development and Commercialization Licenses</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbda2d9b60fb64c5e82c5abf2ff8a795f">

                    <tr>
                      <td style="width: 81.35pt;"><br>
                      </td>
                      <td style="width: 35.65pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Collaboration Products</u></font>. Subject to the terms and conditions of this
                            Agreement, on a Collaboration Program-by-Collaboration Program basis, effective upon the License Effective Date for a particular Collaboration Program in accordance with this Agreement, Ionis grants to Biogen a worldwide,
                            exclusive, royalty-bearing, sublicensable (in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font> below) license under the Licensed Technology to research, Develop,
                            Manufacture, have Manufactured (in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font> below), register, market and Commercialize Collaboration Products under such
                            Collaboration Program in the Field.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">52</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbb74236482d04ed68da9b3268dddcd90">

                    <tr>
                      <td style="width: 81.35pt;"><br>
                      </td>
                      <td style="width: 35.65pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen Alternate Modality Products</u></font>. Subject to the terms and
                            conditions of this Agreement, on a Biogen Alternate Modality Target-by-Biogen Alternate Modality Target basis, effective upon the date Biogen pays Ionis the milestone payment under <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 6.2.2</u></font> for a particular Biogen Alternate Modality Target, Ionis grants to Biogen a worldwide, exclusive, royalty-bearing, sublicensable (in accordance with <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font> below) license under the Licensed Technology to research, Develop, Manufacture, have Manufactured (in accordance with <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 4.1.2</u></font> below), register, market and Commercialize Biogen Alternate Modality Products in the Field.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbd21907127624adeba904a6e713db7c9">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Sublicense Rights; CMO Licenses</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd29187acdcb8436182c23ff2a76de8ce">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the terms and conditions of this Agreement, Biogen will have the right to grant sublicenses under the licenses granted under <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> above and <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.1(b)</u></font> below:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zac4f8fdcc83a487283d1100af56aa3ad">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 27pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">under the Ionis Core Technology Patents, Ionis Product-Specific Patents and Ionis Know-How, to an Affiliate of Biogen or a Third Party; and</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z05a12fe99f5e44d2a41dbea744f92e0e">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 27pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">under the Ionis Manufacturing and Analytical Patents and Ionis Manufacturing and Analytical Know-How, solely to (y) [***] or (z) [***];</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 117pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided </font>that each such sublicense
                will be subject to, and consistent with, the terms and conditions of this Agreement. If, within [***] days of first learning of any breach of such sublicense terms, Biogen fails to take any action to enforce the sublicense terms of a
                sublicense granted pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font>, which failure would cause an adverse effect on Ionis, Biogen hereby grants Ionis the right to enforce such
                sublicense terms on Biogen&#8217;s behalf and will cooperate with Ionis (which cooperation will be at Biogen&#8217;s sole expense and will include, Biogen joining any action before a court or administrative body filed by Ionis against such Sublicensee
                if and to the extent necessary for Ionis to have legal standing before such court or administrative body)<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>in connection with enforcing such terms.
                Biogen will provide Ionis with a true and complete copy of any sublicense granted pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font> within [***] days after the execution thereof.</font></div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">53</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z56c7c231430644358a4bde469ab9db71">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In connection with Biogen&#8217;s selecting and engaging one or more CMOs to supply Clinical Supplies under <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.1(b)</u></font> or after a license is granted under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                                4.1.1</u></font>, or supply API and Finished Drug Product for Commercialization, Ionis will, at Biogen&#8217;s option, either (1) grant a license from Ionis to [***] under the [***] to the extent necessary for [***], which Ionis
                            agrees it will grant to [***], or (2) permit Biogen to grant a sublicense from Biogen to [***]. For Collaboration Products, each such manufacturing agreement between Biogen and a CMO will contain [***]. Biogen will provide Ionis
                            with a true and complete copy of any manufacturing agreement entered into with a CMO within [***] days after the execution thereof. Notwithstanding the foregoing, if Ionis fails to comply with the terms of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2(b)</u></font> and does not cure such failure within 90 days after written notice from Biogen specifying the details of any such failure, Biogen will
                            have the right to [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zba662aee117a4cd788ea2ee61367492f">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Effect of Termination on Sublicenses</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zddb15bdcc0c449a688d0ee628b0b9460">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If this Agreement terminates for any reason, any Sublicensee of Biogen will, from the effective date of such termination, automatically become a direct licensee of
                            Ionis with respect to the rights sublicensed to the Sublicensee by Biogen; <font style="font-size: 10pt; font-family: 'Times New Roman'; 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 Biogen, and (iii) such Sublicensee agrees to
                            pay directly to Ionis such Sublicensee&#8217;s payments under this Agreement to the extent applicable to the rights sublicensed to it by Biogen. Biogen agrees that it will confirm clause (i) of the foregoing in writing at the request
                            and for the benefit of Ionis and if requested, the Sublicensee.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0d3deb5b70d24bf381901799dc188ef3">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If this Agreement terminates for any reason, any Sublicensee of Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.2</u></font> and any Sublicensee of Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>4.5.2</u></font> will, from the effective date of such termination, automatically become a direct licensee with respect to the rights sublicensed to the Sublicensee by the applicable
                            Party hereunder; <font style="font-size: 10pt; font-family: 'Times New Roman'; 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 such Sublicensee, and (iii) with respect to Sublicensees of Ionis, such Sublicensee agrees to pay directly to Biogen
                            such Sublicensee&#8217;s payments under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.4.2</u></font> to the extent applicable
                            to the rights sublicensed to it by Ionis.&#160; Each Party agrees that it will confirm clause (i) of the foregoing in writing at the request and for the benefit of the other Party and if requested, the Sublicensee.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">54</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc769bbc9b1f44d0aaa50ae3382169b21">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>No Implied Licenses</u></font>. All rights in and to Licensed Technology not
                            expressly licensed to Biogen under this Agreement are hereby retained by Ionis or its Affiliates. All rights in and to Biogen Technology not expressly licensed or assigned to Ionis under this Agreement, are hereby retained by
                            Biogen or its Affiliates. Except as expressly provided in this Agreement or to perform Biogen Activities or Ionis Activities, as applicable, 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>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z87404968bb0442eab2651482aa8f3a88">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>License Conditions; Limitations</u></font>. Subject to <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>Section 6.13</u></font>, any license granted under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font>, and the sublicense rights under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font> are subject to and limited by (i) any applicable Third Party Obligations, (ii) the Prior Agreements, and (iii) the Ionis In-License
                            Agreements, in each case to the extent the provisions of such obligations or agreements are specifically disclosed to Biogen in writing (or via electronic data room) prior to the date the applicable license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font> is granted hereunder. With respect to Collaboration Products, Ionis will disclose to Biogen any Third Party Obligations Ionis believes apply
                            to applicable Collaboration Products each time Ionis provides (x) the [***]; (y) the [***]; and (z) the [***], and Biogen will have the right to elect to exclude any Third Party Patent Rights and Know-How to which such Third
                            Party Obligations apply by providing Ionis written notice prior to the License Effective Date with respect to a particular Program. If, prior to the date the applicable license under <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 4.1.1</u></font> is granted hereunder, Biogen provides Ionis with such a written notice to exclude certain Third Party Patent Rights and Know-How from such license, such Third Party Patent Rights
                            and Know-How will not be included in the Licensed Technology licensed with respect to the applicable Products under this Agreement. If Biogen does not provide Ionis with such a written notice to exclude such Third Party Patent
                            Rights and Know-How prior to the date the applicable license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font> is granted hereunder, such Third Party Patent Rights and Know-How
                            (and any Third Party Obligations to the extent applicable to Products) will be included in the Licensed Technology licensed with respect to the applicable Products under this Agreement.</font></div>
                      </td>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z580ef69a27ae4a0abadfaa01d5b803f5">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Trademarks for Products</u></font>. If Biogen is granted a license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font> for a particular Product, to the extent that (i) Ionis owns any trademark(s) specific to such Product which Ionis used prior to the date such
                            license was granted, and (ii) Biogen reasonably believes such trademark(s) would be necessary or useful for the marketing and sale of the applicable Product, then upon Biogen&#8217;s request and at Biogen&#8217;s sole cost and expense
                            relating to such assignment, Ionis will assign its rights and title to such trademark(s) to Biogen or one or more designated Affiliates sufficiently in advance of the First Commercial Sale of the Product to enable Biogen or its
                            Affiliates to offer such Product for sale under such trademark(s).<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>Other than trademarks owned by Ionis prior to the date the applicable
                            license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font> is granted hereunder, Biogen or its designated Affiliate will be solely responsible for developing, selecting, searching,
                            registering and maintaining, and, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4</u></font>, will be the exclusive owner of, all trademarks, trade dress, logos, slogans, designs,
                            copyrights and domain names used on or in connection with Products.</font></div>
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                </table>
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            <div><br>
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            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">55</font></div>
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                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za5e645c2df904b13a7dde0caccdd80ee">

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                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Assignment of Ionis Product-Specific Patents; Grant Back to Ionis</u></font>.</font></div>
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            <div><br>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z45f147a4a5d84cd8bf3a176784e88721">

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                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.2.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Assignment to Biogen</u></font>. After Biogen has obtained the license for a
                            particular Program under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font> and following review and consideration by the Joint Patent Committee, Ionis will assign to Biogen or one or
                            more of its designated Affiliates, Ionis&#8217; ownership interest in (i) all Ionis Product-Specific Patents related to such Program in the Field that are owned by Ionis (whether solely owned or jointly owned with one or more Third
                            Parties), and (ii) any Jointly-Owned Program Patents Covering Products related to such Program, and thereafter Ionis will have no further right to control any aspect of the Prosecution and Maintenance of such Ionis
                            Product-Specific Patents and such Jointly-Owned Program Patents. The assignment of Patent Rights assigned in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.2.1</u></font> will occur within
                            [***] days of Biogen obtaining the applicable license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font>.</font></div>
                      </td>
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                </table>
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            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5e3aa8845d1344f6930dab91f1c5ab8e">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.2.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Grant Back to Ionis</u></font>. Subject to the terms and conditions of this
                            Agreement (including Ionis&#8217; exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 2.1.1</u></font>),
                            Biogen grants to Ionis a worldwide, sublicensable license under any Ionis Product-Specific Patents and Jointly-Owned Program Patents assigned to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                                4.2.1 [***]</u></font>, (b) to conduct its activities with respect to such <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Program </u></font> under the applicable ASO Development Candidate Identification
                            Plans and applicable Initial Development Plans&#160;to the extent permitted by this Agreement, (c) to [***] with respect to such <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Program</u></font> to the extent
                            permitted by this Agreement, (d) to [***] to the extent permitted under <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font> and (e) to exercise Ionis&#8217; rights under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(f)</u></font> (if applicable) or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.2</u></font>.</font></div>
                      </td>
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                </table>
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            <br>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">56</font></div>
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              <div>
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                    <div>
                      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z63434af916c943fcac1c7907fccfb445">

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                            <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.3.</font></td>
                            <td style="width: auto; vertical-align: top; text-align: justify;">
                              <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Enabling Licenses</u></font>.</font></div>
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                  <div style="text-align: justify;">
                    <div>
                      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z777fe5af17c246ab8dfe86d44d43fa79">

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                            <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.3.1.</font></td>
                            <td style="width: auto; vertical-align: top; text-align: justify;">
                              <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Licenses During the Option Period</u></font>.</font></div>
                            </td>
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                  <div><br>
                  </div>
                  <div style="text-align: justify;">
                    <div>
                      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze02d2001226345bab8ce8529557fd18e">

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                            <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                            <td style="width: auto; vertical-align: top; text-align: justify;">
                              <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the terms and conditions of this Agreement, Ionis hereby grants Biogen a worldwide, non-exclusive, sublicensable (but only as permitted in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.2</u></font> below), royalty-free license under the Ionis
                                  Manufacturing and Analytical Know-How and Ionis Manufacturing and Analytical Patents solely to conduct Manufacturing and drug substance process and formulation development activities with respect to any Compound or Product
                                  under any Collaboration Program during the Option Period for such Collaboration Program (including the activities set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule







                                    </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.1(a)</u></font>); <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that the grant of
                                  rights pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.1(a)</u></font> shall not include the
                                  right to Manufacture any Compound or Product for Commercialization purposes.</font></div>
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                      </table>
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                  <div><br>
                  </div>
                </div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb4b70e96a4ce4a57932fc2001f6309c3">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the terms and conditions of this Agreement (including Biogen&#8217;s exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 2.1.1</u></font>), [***] for Biogen to conduct (i) Manufacturing of Compounds or Products under any Collaboration Program or (ii) any Biogen Activities that are Development activities with respect to any
                            Collaboration Program in accordance with this Agreement, in each case ((i) and (ii) during the Option Period), Ionis hereby grants Biogen a worldwide, non-exclusive, sublicensable (but only as permitted in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font> above), royalty-free license under the Licensed Technology. Biogen will [***] arising under any Third Party agreement as a result of granting
                            Biogen the license under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.1(b)</u></font> within [***] days after
                            Biogen&#8217;s receipt of the applicable invoice. For clarity, the grant of rights pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>4.3.1(b)</u></font> shall not include the right to Commercialize any such Collaboration Product or to Manufacture any such Collaboration Product for Commercialization.</font></div>
                      </td>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf9455f3a8b2e4a3ca28642cbc421421c">

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                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.3.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen&#8217;s Right to Sublicense</u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;">.&#160; </font>Biogen will have the right to grant sublicenses under the license granted under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.1(a)</u></font> above (a) in the case of a sublicense of Biogen&#8217;s right to conduct Manufacturing of Compounds or Products, other than any sublicense to conduct
                            manufacturing in support of drug substance process and formulation development activities, solely to (i) [***] or (ii) [***] and (b) in the case of a sublicense of Biogen&#8217;s right to conduct drug substance process and formulation
                            development activities, including manufacturing in support thereof, to any [***].&#160; If, within [***] days after first learning of any breach of such sublicense terms by any such Sublicensee, Biogen fails to take any action to
                            enforce the sublicense terms of a sublicense granted pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.2</u></font>,
                            which failure would cause an adverse effect on Ionis, then Biogen hereby grants Ionis the right to enforce such sublicense terms on Biogen&#8217;s behalf and will cooperate with Ionis (which cooperation will be at Biogen&#8217;s sole
                            expense and will include Biogen joining any action before a court or administrative body filed by Ionis against such Sublicensee if and to the extent necessary to have legal standing before such court or administrative body) in
                            connection with enforcing such terms. Biogen will provide Ionis with a true and complete copy of any sublicense granted to a Third Party pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                              </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.2</u></font> within [***] days after the execution thereof.&#160; For the avoidance of doubt, <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 4.1.3(b)</u></font> shall apply to sublicenses granted under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>4.3.2</u></font>.</font></div>
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            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">57</font></div>
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                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z52f0b877ffb54346bdf4e7e43ff79429">

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                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.3.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div style="font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Enabling </u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;"><u>Licenses to Biogen</u></font>.</font></div>
                      </td>
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                </table>
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            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3d19ef107da34ec89f231e91c7361eb0">

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                      <td style="width: 81pt;"><br>
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                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the terms and conditions of this Agreement (including Biogen&#8217;s exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 2.1.1</u></font>), Ionis hereby grants Biogen an irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the restrictions set forth in <font style="font-size: 10pt; font-family: 'Times
                              New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.3(c)</u></font>) license under any Ionis Program Technology Controlled by Ionis or its Affiliates at any time during the
                            Agreement Term, to research, develop, manufacture, have manufactured and commercialize (i) a product that is being developed or commercialized by Biogen, its Affiliates or its Sublicensee under any Ionis/Biogen Additional
                            Agreement or this Agreement, (ii) products that <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>do not</u></font> include an Oligonucleotide as an active pharmaceutical ingredient, and (iii) Gene-Editing
                            Products. The&#160; licenses in clause (ii) and clause (iii) of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.3(a)</u></font>&#160;and







                            in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.3(b)</u></font>&#160;are royalty-free; <font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-style: italic;">except</font> that if a product that is not a Product is being sold by Biogen, its Affiliates or Sublicensees is Covered by a Target Related Ionis Program Claim in a
                            country, then on a country-by-country basis Biogen will pay to Ionis a royalty equal to [***]% of Net Sales of such product sold by Biogen, its Affiliates or Sublicensees so long as such product is Covered by such Target Related
                            Ionis Program Claim in such country.&#160; A &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Target Related Ionis Program Claim</font>&#8221;<font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-style: italic;">&#160;</font>means a Valid Claim that (A) is within an Ionis Program Patent that is solely owned by Ionis, (B) Covers a product being sold by Biogen, its Affiliates or Sublicensee and (C)
                            claims a gene target, or a method of modulating such gene target to achieve a prophylactic or therapeutic effect/benefit.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb7396da344af4cf6892d80cf3d957a3b">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the terms and conditions of this Agreement (including Biogen&#8217;s exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 2.1.1</u></font>), Ionis hereby grants Biogen an irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the
                            restrictions set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.3(c)</u></font>) license under any Ionis
                            Program Know-How and any Enabled Core Program Patents, in each case, Controlled by Ionis or its Affiliates at any time during the Agreement Term, to research, develop, manufacture, have manufactured and commercialize any
                            product, including products that include an Oligonucleotide as an active pharmaceutical ingredient.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z08f0c1b2f1ee4797a96dac6551e38f50">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen may share any raw data included in the Ionis Program Know-How licensed to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.3(a)</u></font>&#160;and&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.3(b)</u></font>&#160;for use in connection with the performance of its
                            obligations or exercise of its rights under this Agreement or any Ionis/Biogen Additional Agreement, and Biogen may share the conclusions drawn from or based on the review of such raw data with any Third Party. Other than in
                            accordance with the foregoing sentence,&#160; Biogen shall not share with any Third Party that is not an academic or non-profit institution or a contractor acting on Biogen&#8217;s behalf any raw data included in such Ionis Program
                            Know-How or any tangible embodiments thereof to the extent such raw data and tangible embodiments constitute Confidential Information of Ionis.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">58</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z67789dbd575341ed806079c97b2c2436">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.3.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Enabling License to Ionis</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5fb085858096473787b6fe0a4bfb2847">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the terms and conditions of this Agreement (including Ionis&#8217; exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section












                                2.1.1</u></font>), Biogen hereby grants Ionis an irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the restrictions set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.4(c)</u></font>) license under any Biogen Program Technology Controlled by Biogen or its Affiliates at any time during the Agreement Term, other than any Biogen
                            Results licensed to Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.4.1</u></font>, to research, develop,
                            manufacture, have manufactured and commercialize (a) products that include an Oligonucleotide as an active pharmaceutical ingredient (other than products that include an Oligonucleotide that is designed to bind to the RNA that
                            encodes the same target as a product that is being developed or commercialized by Biogen, its Affiliates or Sublicensee under this Agreement or any Ionis/Biogen Additional Agreement) and (b) Gene-Editing Products. The licenses
                            set forth in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.4(a)</u></font>&#160;and in <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.4(b)</u></font>&#160;are royalty-free; <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-style: italic;">except</font> that if a product that is not a Discontinued Product being sold by Ionis, its Affiliates or Sublicensee is Covered by a Target Related Biogen Program Claim in a country, then on a
                            country-by-country basis Ionis will pay to Biogen a royalty equal to [***]% of net sales of such product sold by Ionis, its Affiliates or Sublicensees, for so long as such product is Covered by such Target Related Biogen Program
                            Claim in such country.&#160; For the purpose of the foregoing royalty calculation, &#8220;net sales&#8221; will be calculated [***].&#160; The provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections 6.14.1</u></font>,
                            <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.14.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.14.3</u></font>, <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>6.15</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.16.1</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.16.2(a)</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.16.3</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.17</u></font> shall apply, <font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-style: italic;">mutatis mutandis</font>, to any royalty payments by Ionis to Biogen under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.4</u></font>. A &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Target Related Biogen Program Claim</font>&#8221;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#160;</font>means a Valid Claim that (i) is within a Biogen Program Patent that is solely owned by Biogen, (ii) Covers a product being sold by Ionis, its
                            Affiliates or Sublicensee and (iii) claims a gene target, or a method of modulating such gene target to achieve a prophylactic or therapeutic effect/benefit.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">59</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z38c39375e9654b66b91d43c0254f44fc">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the terms and conditions of this Agreement (including Ionis&#8217; exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 2.1.1</u></font>), Biogen hereby grants Ionis an irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the restrictions set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.4(c)</u></font>) license under any Biogen Program Know-How and any Enabled
                            Core Program Patents, in each case, Controlled by Biogen or its Affiliates at any time during the Agreement Term, to research, develop, manufacture, have manufactured and commercialize any product, including products that do not
                            include an Oligonucleotide as an active pharmaceutical ingredient.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z41b659101f1e46de85bc8a9f137fd813">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis may share any raw data included in the Biogen Program Know-How licensed to Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.3.4(a)</u></font>&#160;and&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.4(b)</u></font>&#160;for use in the performance of its obligations or
                            exercise of its rights under this Agreement or any Ionis/Biogen Additional Agreement, and Ionis may share the conclusions drawn from or based on the review of such raw data with any Third Party. Other than in accordance with the
                            foregoing sentence, Ionis shall not share with any Third Party that is not an academic or non-profit institution or a contractor acting on Biogen&#8217;s behalf any raw data included in such Biogen Program Know-How or any tangible
                            embodiments thereof to the extent such raw data and tangible embodiments constitute Confidential Information of Biogen.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z93c58be1dde14b01aa94d974b5e77a1e">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Licenses to Ionis for Biogen Results</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd5bb9ff7acd2482cb2c0750f0ffa342d">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.4.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the terms and conditions of this Agreement, Biogen hereby grants Ionis an irrevocable, worldwide, non-exclusive, sublicensable license under the Biogen
                            Results Controlled by Biogen or its Affiliate at any time during the Agreement Term, to research, develop, make, have made, import, export, use and sell (a) products that include an Oligonucleotide as an active pharmaceutical
                            ingredient (other than products that include an Oligonucleotide that is designed to bind to the RNA that encodes the same target as a product that is being developed or commercialized by the Parties pursuant to an Option or
                            exclusive license granted from Ionis under this Agreement or the Ionis/Biogen Additional Agreements) and (b) Gene-Editing Products.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7c5861de7c974aacbc421735ebbf792d">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.4.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The license granted in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>4.4.1</u></font> shall be [***] with respect to any [***].&#160; Such license will be [***] with respect to any [***] as follows: on a country-by-country, product-by-product and Biogen Manufacturing Program
                            Patent-by-Biogen Manufacturing Program Patent basis, Ionis will pay to Biogen [***].&#160; If one or more Biogen Manufacturing Program Patents expires, is invalidated or otherwise ceases to Cover a product bearing royalties as set
                            forth above, the applicable royalty rate under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.4.2</u></font> shall
                            be recalculated to reflect the number of Biogen Manufacturing Program Patents then-Covering such product.&#160; For the purpose of the foregoing royalty calculation, [***] will be calculated as follows: [***].&#160; If Ionis grants a
                            sublicense under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.4</u></font> to an entity that is an Ionis
                            Affiliate at the time Ionis grants such sublicense, such applicable sublicense will [***].&#160; The provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.14</u></font> (other than <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.14.4</u></font>), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.15</u></font>, <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 6.16</u></font> (other than <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.16.2(b)</u></font>) and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                                6.17</u></font> shall apply, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">mutatis mutandis</font>, to any royalty payments by Ionis to Biogen under this <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.4.2</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">60</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8fe70527ceb14465b9397a2c2e2cc0c1">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Right to Obtain Direct License from Biogen to Ionis Partner; Sublicensees of
                                Ionis</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf0d6a0125f574a71a9ccd9de146beafe">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.5.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If requested by Ionis, Biogen shall grant a direct, [***] license under the Biogen Results to [***] on the same terms as set forth in <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.4</u></font> with respect to sublicenses of Ionis.&#160; Biogen shall endeavor in good faith to grant such
                            license within [***] days of any such request by Ionis.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf0f800633d6b48f1aee3278f528c3e50">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.5.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will have the right to grant sublicenses under the licenses granted under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.4</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided </font>that each such sublicense will be subject to, and
                            consistent with, the terms and conditions of this Agreement. If, within [***] days after first learning of any breach of such sublicense terms, Ionis fails to take any action to enforce the sublicense terms of a sublicense
                            granted pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.5.2</u></font>, which failure would cause an
                            adverse effect on Biogen, Ionis hereby grants Biogen the right to enforce such sublicense terms on Ionis&#8217; behalf and will cooperate with Biogen (which cooperation will be at Ionis&#8217; sole expense and will include, Ionis joining
                            any action before a court or administrative body filed by Biogen against such Sublicensee if and to the extent necessary for Biogen to have legal standing before such court or administrative body)<font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>in connection with enforcing such terms. Ionis will provide Biogen with a true and complete copy of any sublicense granted pursuant to this <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.5.2</u></font> within [***] days after the execution thereof.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z65b9aa4f992641cdb9653e839d0a4a01">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ownership of and Assistance with Regulatory Filings</u></font>. If requested by
                            Biogen, Ionis&#8217; and Biogen&#8217;s regulatory teams will meet and begin to prepare a plan, which plan will be completed no later than [***] prior to such anticipated filing date, for drafting and reviewing the sections of the NDA and
                            MAA for the applicable Collaboration Product (including establishing responsibilities for drafting and reviewing common technical document (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                              font-style: italic;">CTD</font>&#8221;) modules, authorship, plan activity timelines and associated costs and expenses) and assigning&#160; all necessary filings with any Regulatory Authority related to the applicable Collaboration
                            Product to Biogen to ensure a smooth transition to Biogen, accelerate CTD completion and facilitate rapid NDA and MAA filing. Each CTD will be consistent with the Specific Performance Milestone Events for the applicable
                            Collaboration Program.&#160; The Parties regulatory teams will submit such plan to the CSC, if still active.&#160; The Parties will act in good faith and mutually agree upon each such plan, <font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-style: italic;">provided, however</font>, that, after exercising an Option for the applicable Collaboration Program, Biogen will have final decision-making authority with respect to the [***]. Once such
                            plan is complete, each Party will use Commercially Reasonable Efforts to execute their respective tasks and responsibilities under such plan in the time frames set forth in such plan. After exercising an Option for a particular
                            Collaboration Program, if Biogen requests, Ionis will assist Biogen in preparing regulatory filings for the Collaboration Product, under terms negotiated in good faith between Ionis and Biogen, including payment for Ionis&#8217; time
                            at Ionis&#8217; then applicable FTE Rate plus any reasonable out of pocket expenses incurred by Ionis in providing such assistance, utilizing the payment mechanism set forth in <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 1.14.1</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">61</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z42840477ddee4f819c472c0d050949fc">

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                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Subcontracting</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zad0c19bb3fe44184b4f5101f96c94d24">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.7.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the terms of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>4.7</u></font>, each Party will have the right to engage Third Party subcontractors to perform certain of its obligations under this Agreement. Any subcontractor to be engaged by a Party to perform a
                            Party&#8217;s obligations set forth in the Agreement will meet the qualifications typically required by such Party for the performance of work similar in scope and complexity to the subcontracted activity and will enter into such
                            Party&#8217;s standard nondisclosure agreement consistent with such Party&#8217;s standard practices. Any Party engaging a subcontractor hereunder will remain responsible and obligated for such activities and will not grant rights to such
                            subcontractor that interfere with the rights of the other Party under this Agreement. Each Party will be responsible for any income or non-income taxes that arise as a result of such Party&#8217;s use of any Third Party subcontractors
                            hereunder, including payroll, income, withholding, sales and use, VAT, customs, duties excise or property taxes, and such taxes will not be reimbursable expenditures.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0a15f9160cc443ccaf2fbe04fbc44def">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.7.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis agrees that, where Biogen wishes to (sub)contract with a Third Party with respect to any of the rights granted under <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.1(a)</u></font>, Ionis shall, within [***] days of any request by Biogen, provide Biogen with a
                            letter of authorization as necessary for Biogen to be able to contract with such Third Party in accordance with the terms of this Agreement.&#160; Biogen will ensure that any Third Party (sub)contractors Biogen uses to conduct the
                            process development or manufacturing activities contemplated by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.1(a)</u></font>
                            will be obligated to assign to Biogen all right, title and interest in and to any inventions developed by such (sub)contractors in the performance of such activities.&#160; For clarity, solely with respect to the Biogen Results, this
                            <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.7.2</u></font> shall supersede and replace <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 7.1.3</u></font> of this Agreement to the extent of any conflict.&#160; Biogen 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, diminishes or encumbers the rights granted to Ionis under the Manufacturing Process Development Terms. In addition, after the First Amendment Date, Biogen will
                            use reasonable efforts to include, in any agreement with a (sub)contractor that has substantial material obligations related to the Development, Manufacture or Commercialization of a Product, provisions requiring that, in the
                            event the applicable Option is terminated, expires unexercised or this Agreement is terminated, such (sub)contractor would enter into an agreement with Ionis with respect to such Product that is substantially similar to such
                            (sub)contractor&#8217;s agreement with Biogen and would reasonably cooperate with Ionis to facilitate the transition of such Product to Ionis following such termination or Option expiration, including the transfer to Ionis of data and
                            information in such (sub)contractor&#8217;s possession related to the Product.</font></div>
                      </td>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">62</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z359eefd74929464995a5cdcd45750629">

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                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.8.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Technology Transfer</u></font>. </font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zeb5ac66a906c40f29e595b9691adf084">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.8.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Technology Transfer to Biogen during the Option Period</u></font>. Within [***]
                            days after the First Amendment Date, Ionis will deliver to Biogen or one or more designated Affiliates, solely for use by Biogen, [***] to conduct any Biogen Activities that are Development activities with respect to any High
                            Interest Target or Collaboration Target in accordance with this Agreement, all Ionis Manufacturing and Analytical Know-How in Ionis&#8217; Control [***] to conduct such Biogen Activities. If requested by Biogen, Ionis will provide
                            Biogen with a reasonable level of assistance in connection with such transfer, which Biogen will reimburse Ionis for its time incurred in providing such assistance at the then-applicable Ionis FTE Rate, plus any reasonable
                            out-of-pocket expenses incurred by Ionis in providing such assistance, using the payment mechanism set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9b274f59786a4a5287914197d5b739ed">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.8.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Technology Transfer to Biogen after </u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;"><u>the License Effective Date</u></font>. On a Collaboration Program-by-Collaboration Program basis, Ionis will promptly, but no later than [***] after the License Effective
                            Date with respect to a Collaboration Program, deliver to Biogen or one or more designated Affiliates:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">63</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2b8cfda00c56485092d79f670f003770">

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                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis Know-How</u></font>. All Ionis Know-How in Ionis&#8217; possession that has not
                            previously been provided hereunder, for use solely in accordance with the licenses granted under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font> and <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 10.4.2</u></font>, and Ionis will and does hereby assign to Biogen all of Ionis&#8217; right, title and interest in and to the IND for the applicable Development Candidate, together with
                            all Regulatory Materials (including drafts) that relate to the applicable Development Candidate; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that</font>, (i) notwithstanding the
                            foregoing, and subject to the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1</u></font>, the Parties acknowledge that Ionis shall be permitted to use excerpts or portions of any such
                            assigned Regulatory Materials in any other regulatory submissions, notifications, registrations, approvals and/or other filings and correspondence made to or with a Regulatory Authority in any country or jurisdiction related to
                            products other than the Development Candidate, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, further that </font>such excerpts or portions shall not include (A) any non-public
                            data or information, in each case, related solely to the applicable Development Candidate, or (B) any Confidential Information of Biogen, and (ii) for clarity, such assignment of Ionis&#8217; right, title and interest in and to such
                            Regulatory Materials shall not include the assignment of any Know-How (including any data) contained therein. If Ionis intends to use any excerpt or portion of any such assigned Regulatory Materials in accordance with clause (i)
                            of the preceding sentence that are not in the public domain and do not relate to Ionis&#8217; antisense oligonucleotide chemistry platform, Ionis shall, at least [***] days in advance of the anticipated submission of such excerpt or
                            portion to a Regulatory Authority, notify Biogen of such intent and provide to Biogen a copy of such proposed excerpt or portion for review and comment. The Parties shall discuss in good faith any comments of Biogen with respect
                            to such proposed excerpt or portion prior to submission thereof. To assist with the transfer and assignment of such Ionis Know-How, Ionis will make its personnel reasonably available to Biogen during normal business hours for up
                            to [***] ([***]) of Ionis&#8217; time for each Collaboration Program to transfer such Ionis Know-How under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>4.8.2(a)</u></font>. Thereafter, if requested by Biogen, Ionis will provide Biogen with a reasonable level of assistance in connection with such transfer, which Biogen will reimburse Ionis
                            for its time incurred in providing such assistance at the then-applicable Ionis FTE Rate, plus any reasonable out-of-pocket expenses incurred by Ionis in providing such assistance, using the payment mechanism set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>.</font></div>
                      </td>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf9a16374f9e940f3afecb821d8333f4a">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis Manufacturing and Analytical Know-How</u></font>. Solely for use by
                            Biogen, its Affiliates or a Third Party acting on Biogen&#8217;s behalf to Manufacture API in Biogen&#8217;s own or an Affiliate&#8217;s manufacturing facility, all Ionis Manufacturing and Analytical Know-How in Ionis&#8217; Control relating to
                            applicable Products, which is necessary for the exercise by Biogen, its Affiliates or a Third Party of the Manufacturing rights granted under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font>.
                            Upon Biogen&#8217;s request, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font>, Ionis will provide up to [***] for [***] ([***]) of its time for each Collaboration Program to
                            transfer such Ionis Manufacturing and Analytical Know-How under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8.2(b)</u></font>
                            to any Third Party Manufacturing API, Clinical Supplies or Finished Drug Product on Biogen&#8217;s behalf solely to Manufacture API, Clinical Supplies or Finished Drug Product in accordance with the terms of this Agreement.
                            Thereafter, if requested by Biogen, Ionis will provide Biogen with a reasonable level of assistance in connection with such transfer, which Biogen will reimburse Ionis for its time incurred in providing such assistance at the
                            then-applicable Ionis FTE Rate, plus any reasonable out-of-pocket expenses incurred by Ionis in providing such assistance, using the payment mechanism set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                                1.14.1</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">64</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zaa4a981c22764239bd6e00928f045040">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>API and Product</u></font>.<font style="font-size: 10pt; font-family: 'Times
                              New Roman'; font-weight: bold;">&#160;</font>Upon Biogen&#8217;s written request, Ionis will sell to Biogen any bulk API, Clinical Supplies and Finished Drug Product in Ionis&#8217; possession at the time of the License Effective Date with
                            respect to such Collaboration Program, at a price equal to [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4d04b7e83a854135be387f8d034b86f6">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Trial Master File</u></font>.&#160; Upon Biogen&#8217;s written request, Ionis will
                            provide to Biogen or its designated Affiliate a copy of Ionis&#8217; trial master file for such Collaboration Program (such trial master file, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                              font-style: italic;">Trial Master File</font>&#8221;) promptly, and in any event within [***] days after Ionis&#8217; receipt of such written request. Within [***] days after receipt of the Trial Master File, Biogen or an Affiliate may
                            notify Ionis of any omissions or deficiencies that Biogen or its Affiliate believes in good faith cause the Trial Master File to be incomplete (such notice, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-weight: bold; font-style: italic;">Trial Master File Deficiency Notice</font>&#8221;). Ionis will promptly, and in any event within [***] days after receipt of the Trial Master File Deficiency Notice, resubmit a complete Trial
                            Master File to Biogen or its designated Affiliate, including any information required to be included in a Trial Master File that Biogen requests be included in the Trial Master File. If the Parties do not agree as to whether the
                            Trial Master File is complete, the matter will be referred to the Executives for resolution. The Executives will meet promptly and negotiate in good faith to resolve the dispute and agree upon a complete Trial Master File. If
                            Ionis is the Commercializing Party of a Discontinued Collaboration Product, this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>4.8.2(d)</u></font> will apply to such Discontinued Collaboration Product <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">mutatis mutandis</font> such that Biogen will transfer
                            to Ionis Biogen&#8217;s trial master file for such Discontinued Collaboration Product.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za3e30baa546948c38c53bc10d39a9006">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.8.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Results</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7f99563ac1d94ec3a1bc250799a840f3">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Each Party shall share with the other Party on an Annual basis (preferably at in-person meetings) the results of such Party&#8217;s manufacturing process development
                            activities, including all data, the identity and location of vendors, information and results received from vendors, and planned additional work, (a) in the case of Biogen, to the extent arising under the Manufacturing Process
                            Development Terms (all Know-How and Patent Rights within the foregoing, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Results</font>&#8221;) and (b) in the case of
                            Ionis, to the extent arising under or otherwise subject to a disclosure obligation of Ionis under this Agreement, (all Know-How and Patent Rights within the foregoing, the &#8220;<font style="font-size: 10pt; font-family: 'Times New
                              Roman'; font-weight: bold; font-style: italic;">Ionis Results</font>&#8221; and, collectively with the Biogen Results, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Results</font>&#8221;).&#160;











                            All intellectual property matters with respect to the Results, including any Patent Rights therein, will be governed by the intellectual property provisions of this Agreement, and the Know-How and Patent Rights included in the
                            Ionis Results shall constitute Ionis Manufacturing and Analytical Know-How and Ionis Manufacturing and Analytical Patent Rights, respectively, under this Agreement.&#160; If requested by either Party, Biogen and Ionis will establish
                            a manufacturing committee to facilitate the exchange of Results between the Parties.&#160; For clarity, Biogen shall have the right, in its sole discretion, to determine whether to seek patent protection for any Biogen Results that
                            are not jointly owned with Ionis, and Biogen shall control and be responsible for all aspects of the Prosecution and Maintenance of any Patent Right within such Biogen Results (each, a &#8220;<font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Manufacturing Program Patent</font>&#8221;) in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.2(c)</u></font> of this
                            Agreement.&#160; Biogen shall notify Ionis within [***] days if Biogen files a patent application Controlled by Biogen or its Affiliates that claims any Biogen Results and shall provide Ionis with a copy of such patent application.&#160;
                            Ionis will have no obligation to incorporate any Biogen Results into Ionis&#8217; manufacturing processes.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">65</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1abc82ed13af4a0f847aac96bf57f49d">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">For clarity, the Manufacturing Process Development Terms, and not the enabling licenses set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section












                              </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.3</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>4.3.4</u></font>, shall govern with respect to all Results.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">ARTICLE 5.</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z65710022ba884d5890d1449ce4fc3264">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen Diligence</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za0b1c05be7d04c59bc53207b15d18565">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Collaboration Products</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze45f914bb633469b9aadab8b8264e666">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Prior to the License Effective Date with respect to a Collaboration Program, Biogen will use Commercially Reasonable Efforts to conduct (i) any Biogen Activities on
                            the timeline set forth in the applicable Neurology Plan, (ii) except as provided under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(c)(ii)</u></font>, for each ALS Collaboration Program all
                            activities under each Initial Development Plan on the timeline set forth in the applicable Initial Development Plan, and (iii) except as provided under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                                1.10.2(c)(ii)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.4(a)</u></font>, for each Biogen Conducted Non-ALS Collaboration Program all activities under each Initial
                            Development Plan on the timeline set forth in the applicable Initial Development Plan. Without limiting the foregoing, Biogen may discontinue Development under such an Initial Development Plan if after having consulted, and
                            having given good faith consideration to the recommendations of the Neurology JDC and a mutually-agreed Third Party expert, Biogen in good faith believes that continuing such Development would (1) pose an unacceptable risk or
                            threat of harm in humans, or (2) violate any Applicable Law, ethical principles, or principles of scientific integrity, in which case Biogen will provide Ionis with reasonable advance notice of such discontinuation, including
                            the grounds for Biogen&#8217;s determination, and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.3</u></font> will apply.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">66</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9335a7835bc3422681fcaacd67d1734e">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Following the License Effective Date with respect to a Collaboration Program, Biogen will be 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 applicable Products; and Biogen will use Commercially Reasonable Efforts to
                            Develop, Manufacture and Commercialize at least one Product from each Collaboration Program for which an Option has been exercised.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z34d3c514262143b6998e373edb33648b">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen Alternate Modality Products</u></font>. Following the date a license is
                            granted to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> for a particular Biogen Alternate Modality Product, Biogen will be 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 applicable Biogen Alternate Modality Products; and Biogen
                            will use Commercially Reasonable Efforts to develop, manufacture and commercialize at least one Biogen Alternate Modality Product for each Biogen Alternate Modality Target.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdf50c9189d494004a1e79927e948327e">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Multi-Indication Targets for Non-Neurological Indications</u></font>. Without
                            limiting any of the foregoing, with respect to any plan for the development and commercialization of a Multi-Indication Target Biogen has agreed to conduct pursuant to a plan mutually-agreed under <font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>, Biogen will use Commercially Reasonable Efforts to develop, manufacture and commercialize at least one Product for such Multi-Indication
                            Target in accordance with such agreed plan.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdd2beed2553243b0ad9064987b9472a8">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Specific Performance Milestone Events for Collaboration Products</u></font>.
                            Without limiting any of the foregoing, (i) after the License Effective Date for a Collaboration Program that is not an ALS Collaboration Program, and (ii) following the designation of the Development Candidate for an ALS
                            Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, Biogen will use Commercially Reasonable Efforts to achieve the specific performance milestone events set forth in <font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 5.1.4</u></font>, as such schedule may be updated from time to time in
                            accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(d)</u></font> (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Specific
                              Performance Milestone Events</font>&#8221;) for a Collaboration Product on the timeline set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 5.1.4</u></font>; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">67</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd8700be15eb64bfaa41ca42250105453">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Development Results under ALS Collaboration Programs and Biogen Conducted
                                Non-ALS Collaboration Programs</u></font>.&#160; Without limiting the other provisions of this Agreement, promptly following its generation or receipt of the results of a [***] or a Clinical Study under an ALS Collaboration
                            Program or a Biogen Conducted Non-ALS Collaboration Program, as applicable, Biogen will provide Ionis (i) all study reports from [***] studies for the applicable Collaboration Product that are intended to support an
                            investigational new drug application, (ii) all study reports for any pre-clinical and clinical trials conducted by Biogen for such Collaboration Product, (iii) the data generated under the [***] for the applicable PoC Trial(s),
                            and (iv) copies of all filings submitted to Regulatory Authorities regarding such Collaboration Product.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z55bb1a0c8c05443dbbccf2b88d982a79">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Integrated Development Plan for Products</u></font>. On a Product-by-Product
                            basis, Biogen will prepare a Development and global integrated Product plan outlining key aspects of the Development of each Product through Approval as well as key aspects of worldwide regulatory strategy, market launch, and
                            Commercialization, including Product sales forecasts (each, an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Integrated Development Plan</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">IDP</font>&#8221;). Biogen will prepare the IDP no later than (i) [***] after the License Effective Date with respect to a Collaboration
                            Program or (ii) after the First Commercial Sale of a Biogen Alternate Modality Product, and the IDP will include information consistent in scope and content with the information Biogen&#8217;s senior management uses for internal
                            decision-making for such Product. <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 5.1.6</u></font>
                            sets forth examples of the types of information Biogen expects will be available to include in the IDP at different stages of development and commercialization. Once Biogen has prepared such plans, Biogen will update the IDP
                            consistent with Biogen&#8217;s standard practice and provide such updates to the CSC [***] (or Ionis after the CSC terminates under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.5)</u></font>. Biogen
                            and Ionis will meet [***] basis to discuss the draft of the IDP and Biogen will consider, in good faith, any proposals and comments made by the CSC (or Ionis after the CSC terminates under <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 1.18.5)</u></font> for incorporation in the final IDP. Notwithstanding the foregoing, Biogen&#8217;s obligations to provide Ionis with information or reports with respect to a Product
                            under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1.6</u></font> will terminate if [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6f1130537ea8446cb016c9d440eddc53">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Investigator&#8217;s Brochure for Collaboration Products</u></font>. After the
                            License Effective Date with respect to a Collaboration Program, Ionis will provide to Biogen an up-to-date version of the Investigator&#8217;s Brochure for the applicable Collaboration Product. Biogen will keep Ionis reasonably
                            informed with respect to the status, activities and progress of Development of Collaboration Products by providing updated versions of the Investigator&#8217;s Brochure for each Collaboration Product to Ionis [***] and when
                            Development of such Collaboration Product results in any substantive change to the safety or risk to the Collaboration Product. Biogen&#8217;s obligations under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                                5.1.7</u></font> will terminate with respect to a Collaboration Product if [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">68</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z31671c59ce3c49f2a953a72579cf025d">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1.8.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Applicable Laws</u></font>. Biogen 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb0d5d1e60838443b906c5d836442bebb">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Regulatory Matters; Global Safety Database; Pharmacovigilance Agreement</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9b0ae15d2c504d078176c686ff9a7c92">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.2.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>IND-Holder</u></font>. Subject to this <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 5.2</u></font>, for Collaboration Programs that are not ALS Collaboration Programs or Biogen Conducted Non-ALS Collaboration Programs, Ionis will be the IND-holder and will be
                            responsible for all communications with Regulatory Authorities regarding such Collaboration Programs prior to the applicable License Effective Date.&#160; Subject to this <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 5.2</u></font>, for ALS Collaboration Programs and Biogen Conducted Non-ALS Collaboration Programs, Biogen will be the IND-holder and will be responsible for all communications with Regulatory Authorities
                            regarding such ALS Collaboration Programs and Biogen Conducted Non-ALS Collaboration Programs.&#160; Biogen will be the IND-holder after the applicable License Effective Date for each Collaboration Program in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3</u></font>, and, except as otherwise provided in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.2</u></font>, shall
                            thereafter have sole decision-making authority with respect to the matters set forth in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.2</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf2d63142845447f9893f0c72ef158d04">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.2.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Pharmacovigilance Agreement</u></font>. As soon as reasonably practicable
                            following designation of a particular Development Candidate, and in any event no later than [***] prior to the date on which Ionis or Biogen anticipates filing an IND for the associated Collaboration Product with a Regulatory
                            Authority, the Parties will enter into a Safety Drug Exchange Agreement relating to the collection, review, assessment, tracking, exchange and filing of information related to adverse events associated with such Collaboration
                            Product occurring prior to the First Commercial Sale in any country on terms substantially the same as the terms of the Safety Drug Exchange Agreement to be entered into by the Parties with respect to adverse events associated
                            with products developed under the Ionis/Biogen Additional Agreements. In addition, following the First Amendment Date the Parties will discuss in good faith the possibility of entering into a single Safety Drug Exchange
                            Agreement with respect to all activities under this Agreement and the Ionis/Biogen Additional Agreements. No later than [***] days prior the date on which Biogen reasonably anticipates that it will exercise an Option, Biogen
                            will so notify Ionis and the pharmacovigilance departments of each of Ionis and Biogen will meet and determine the approach to be taken for the collection, review, assessment, tracking, exchange and filing of information related
                            to adverse events associated with the applicable Collaboration Product occurring after such First Commercial Sale, consistent with the provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                                5.2</u></font>. Such approach will be documented in a separate and appropriate written pharmacovigilance agreement between the Parties which will control with respect to the subject matter covered therein (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pharmacovigilance Agreement</font>&#8221;). Such agreement will specify that the owner of the IND for a Collaboration Product will be
                            the global commercial safety database owner for such Collaboration Product with primary responsibility for maintaining such database, and that Ionis will be and remain the owner of the Ionis Internal ASO Safety Database with
                            primary responsibility for maintaining such database. Such agreement will also specify that, prior to the License Effective Date for a particular Collaboration Program, the Parties will communicate updates on safety data
                            regarding a Collaboration Product to Biogen through monthly telephone calls between the drug safety representatives of Biogen and Ionis.&#160; Biogen and Ionis will jointly review and discuss safety issues arising under any
                            Collaboration Program that may have implications on any Initial Development Plan for such Collaboration Program. Biogen may suggest actions to address Collaboration Product safety data or audit findings, and Ionis will consider
                            all such suggestions in good faith. The Pharmacovigilance Agreement will be in accordance with, and will enable the Parties and their Affiliates or licensees or Sublicensees, as applicable, to fulfill, local and international
                            regulatory reporting obligations to Regulatory Authorities and other Applicable Law.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">69</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc0dbaee035204d2e8fd8f2b6e81f6543">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.2.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Regulatory Communications Regarding Clinical Study Trial Designs</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z98bc1df11c7745b797898862f69fee24">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Party who is the IND-holder will not initiate discussions with a Regulatory Authority regarding the [***] for a Collaboration Program until such [***] have been
                            established pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(d)</u></font>, as applicable.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd05fd2736a584c458e5723e5214a6a53">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">With respect to a Collaboration Program, to the extent practical, prior to any scheduled meeting with a Regulatory Authority regarding the [***] for such
                            Collaboration Program, (i) the applicable Neurology JDC (or the Parties, if Ionis ceases its participation in such Neurology JDC under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.5</u></font>)
                            will discuss and mutually agree upon the approximate timing and objectives for such meeting and (ii) the Party who is the IND-holder will provide the other Party with (A) an invitation to attend at least [***] and (B) an [***]
                            with the IND-holder. In addition, the IND-holder will allow the other Party to participate in any such meeting under the direction of The IND-holder<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style:
                              italic;"> provided, however</font>, that the IND-holder may exclude such other Party from any portion of such meeting that does not pertain to such Collaboration Program.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zde83695d77964b6a9021fd121741d618">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">With respect to a Collaboration Program, in each case, to the extent regarding the [***] for such Collaboration Program, the Party who is the IND-holder will
                            promptly provide the other Party with (i) final copies of all material correspondence with and submission to any Regulatory Authority promptly following submission thereof, (ii) a [***] from a Regulatory Authority, and (iii) a
                            [***] with a Regulatory Authority.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">70</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z77fafb529f4d4dbaa41f6893da45d4df">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">With respect to a Collaboration Program, the Party who is the IND-holder will provide the other Party with [***] any Regulatory Authority that materially impact the
                            [***] for such Collaboration Program sufficiently [***] to the applicable Regulatory Authority to enable the other Party to have a meaningful [***] thereof.&#160; The [***] any Regulatory Authority must reflect the Initial
                            Development Plan. The applicable Neurology JDC (or the Parties if Ionis ceases its participation in such Neurology JDC under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.5</u></font>) will
                            [***] on the [***]; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that if [***] prior to a Regulatory Authority&#8217;s requirement for a response as determined by [***] will
                            consider in good faith [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zde8dd864683641ee814438f0a2e40057">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.2.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Participation in Regulatory Meetings for Collaboration Products</u></font>.
                            With respect to a Collaboration Program, each Party will provide the other Party with as much advance written notice as practicable of any meetings that such first Party has or plans to have with a Regulatory Authority regarding
                            pre-approval or Approval matters for a Collaboration Product under such Collaboration Program or that directly relate to Ionis&#8217; antisense oligonucleotide chemistry platform, and will allow two representatives of the other Party
                            to participate in any such meetings under the direction of such first Party;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"> provided, however</font>, that, if such first Party is Ionis, Ionis
                            may exclude Biogen from any portion of such meeting that does not pertain to such Collaboration Product; and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided,</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">further</font>, that, if such first Party is Biogen, Biogen may exclude Ionis from any portion of such meeting that does not pertain to such
                            Collaboration Product or to Ionis&#8217; antisense oligonucleotide chemistry platform.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z91a67fa211d24b7380d4a212e93196ee">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.2.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Regulatory Communications for Collaboration Products</u></font>. With respect
                            to a Collaboration Program, each Party will promptly provide the other Party with copies of documents and communications submitted to (including drafts thereof) and received from Regulatory Authorities [***] that materially
                            impact the Development or Commercialization of Collaboration Products under such Collaboration Program for such other Party&#8217;s review and comment, and such first Party will consider in good faith including any comments provided
                            by such other Party to such documents and communications.&#160; Each Party will promptly notify the other Party upon receipt of any such documents or communications from any Regulatory Authority [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4157031972e247e09ee139710f1d52b9">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.2.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Class Generic Claims for Collaboration Products</u></font>. To the extent
                            Biogen intends to make any claims in a Collaboration Product label or regulatory filing that are class generic to ASOs, Biogen will provide such claims and regulatory filings to Ionis in advance and will consider in good faith
                            any proposals and comments made by Ionis, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Biogen is not obligated to incorporate such proposals and comments in
                            any such claims and regulatory filings.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">71</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zeafa0f48e8fe44b38d21ce30a3fcd9c9">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.2.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Antisense Safety Database</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z48691e313ab44ef79f47e43227a414fe">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Internal ASO Safety Database</font>&#8221;). In an effort to
                            maximize understanding of the safety profile and pharmacokinetics of Ionis compounds, Biogen will cooperate in connection with populating the Ionis Internal ASO Safety Database. To the extent collected by Biogen and in the form
                            in which Biogen uses/stores such information for its own purposes, Biogen will provide Ionis with information concerning toxicology, pharmacokinetics, safety pharmacology study(ies), serious adverse events and other safety
                            information related to Collaboration Product as soon as practicable following the date such information is available to Biogen (but not later than [***] days after Biogen&#8217;s receipt of such information). In connection with any
                            reported serious adverse event, Biogen will provide Ionis all serious adverse event reports, including initial, interim, follow-up, amended, and final reports. In addition, with respect to Collaboration Product, Biogen will
                            provide Ionis with copies of Annual safety updates filed with each IND and the safety sections of any final Clinical Study reports within [***] days following the date such information is filed or is available to Biogen, as
                            applicable. Furthermore, Biogen will promptly provide Ionis with any supporting data and answer any follow-up questions reasonably requested by Ionis. All such information disclosed by Biogen to Ionis will be Biogen Confidential
                            Information; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Ionis may disclose any such Biogen Confidential Information to (i) Ionis&#8217; other partners pursuant to
                            <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.2.7(b)</u></font> below if such information is regarding class generic properties of ASOs, or (ii) any Third Party, in each case, so long as Ionis does
                            not disclose the identity of a Collaboration Product or Biogen. Biogen will deliver all such information to Ionis for the Ionis Internal ASO Safety Database to Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad,
                            California 92010, Attention: Chief Medical Officer (or to such other address/contact designated in writing by Ionis). Biogen will also cause its Affiliates and Sublicensees to comply with this <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 5.2.7(a)</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
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            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zcefc6b1614744175a889e4e33b7f41d6">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">From time to time, Ionis utilizes the information in the Ionis Internal ASO Safety Database to conduct analyses to keep Ionis and its partners informed regarding
                            class generic properties of ASOs, including with respect to safety. As such, if and when Ionis identifies safety or other related issues that may be relevant to a Collaboration Product (including any potential class-related
                            toxicity), Ionis will promptly (and in no event later than five Business Days following identification by Ionis) inform Biogen of such issues and, if requested, provide the data supporting Ionis&#8217; conclusions.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">72</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z33efc93c5364458892cf2a02f83a3790">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Research and Manufacturing Records</u></font>. Each Party shall maintain,
                            consistent with its then-current internal policies and practices, and cause its employees and subcontractors to maintain, consistent with its internal policies and Applicable Law, for at least ten years, records and laboratory
                            notebooks, inventory, purchase and invoice records and Manufacturing records in each case with respect to the Collaboration Products in sufficient detail and in a good scientific manner appropriate for (i) inclusion in filings
                            with Regulatory Authorities for such Collaboration Products, and (ii) obtaining and maintaining intellectual property rights and protections, including Patent Rights for such Collaboration Products. Such records and laboratory
                            notebooks shall be complete and accurate in all material respects and shall fully and properly reflect all work done, data and developments made, and results achieved.&#160; Each Party shall allow the other Party, to the extent
                            necessary for such regulatory or intellectual property protection purposes, to inspect or copy such records, subject to redaction by such Party.</font></div>
                      </td>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3a560ce14e2a43dba3c468fdc7a99f6f">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Product Development Plans for ALS Collaboration Programs and Biogen Conducted
                                Non-ALS Collaboration Programs</u></font>. With respect to each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program, Biogen shall propose and develop a product development plan, which shall
                            govern CMC-related matters for the applicable Collaboration Product.&#160; Ionis shall have the opportunity to review and comment on each such product development plan and Biogen shall consider any such comments in good faith.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 6.</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">FINANCIAL PROVISIONS</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zcd02f2f87bbe4095bd2d0c91097dcb24">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Up-Front Fee</u></font>. Within five Business Days following the Effective
                            Date, Biogen will pay Ionis an up-front fee of $100,000,000.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0e4b249ee1db4a8dac6d143e2d3cc1b5">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Drug Discovery Milestone Payments</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4bd9a755393c42798c5ebecf489b7052">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.2.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Collaboration Targets</u></font>. For each Collaboration Program, after (a) a
                            Collaboration Target is designated under this Agreement, and (b) Ionis begins designing human development candidates under such Collaboration Program for human candidate screening under the applicable ASO Development Candidate
                            Identification Plan ([***]), Ionis will so notify Biogen (such notice, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Design Notice</font>&#8221;) and Biogen will pay Ionis a
                            milestone payment equal to (i) $[***] for Collaboration Programs that are not ALS Collaboration Programs [***], subject to any applicable credits permitted by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section












                                1.8.3</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.4</u></font>, (ii) $[***] for ALS Collaboration Programs [***], or (iii) $[***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">73</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze9108f283a5f4b9c829ecd8aa8cd01d8">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.2.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen Alternate Modality Targets</u></font>. On a Biogen Alternate Modality
                            Target-by-Biogen Alternate Modality Target basis, each time a Neurology Target is designated a Biogen Alternate Modality Target under this Agreement, Biogen will pay Ionis a milestone payment equal to $[***], subject to any
                            applicable credits permitted by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.3</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.4</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze37ee511cf9748fa8cd20e3ec3050327">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Milestone Payments for Achievement of Milestone Events by Biogen Alternate
                                Modality Products</u></font>. Subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.3(b)</u></font>, for each Biogen Alternate Modality Target, Biogen will pay to Ionis the milestone
                            payments as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table X</u></font> below when a milestone event (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times
                              New Roman'; font-weight: bold; font-style: italic;">Biogen Alternate Modality Milestone Event</font>&#8221;) listed in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table X</u></font>
                            is first achieved by a Biogen Alternate Modality Product related to such Biogen Alternate Modality Target:</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <div>
              <table cellspacing="0" cellpadding="2" border="0" align="center" style="border-collapse: collapse; width: 90%; font-family: &quot;Times New Roman&quot;; font-size: 10pt;" id="zf82a4589190747c7ae7b1c2d62229c27">

                  <tr>
                    <td colspan="2" style="vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0);">
                      <div style="text-align: center; font-weight: bold;"><font style="font-variant: small-caps; font-family: 'Times New Roman'; font-size: 10pt;"><u>Table X</u></font></div>
                    </td>
                  </tr>
                  <tr>
                    <td style="width: 45%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
                      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Biogen Alternate Modality Milestone </font></div>
                      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Event</font></div>
                    </td>
                    <td style="width: 45%; vertical-align: middle; border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0);">
                      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Milestone Event Payment per Biogen </font></font></div>
                      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Alternate Modality Target</font></font></div>
                    </td>
                  </tr>
                  <tr>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                      [***] </td>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); font-family: &quot;Times New
                      Roman&quot;; font-size: 10pt; text-align: left;"> $[***] </td>
                  </tr>
                  <tr>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(255, 255, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
                      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">[***]</font></font></div>
                    </td>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(255, 255, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); font-family: &quot;Times New
                      Roman&quot;; font-size: 10pt; text-align: left;"> $[***] </td>
                  </tr>
                  <tr>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                      [***] </td>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); font-family: &quot;Times New
                      Roman&quot;; font-size: 10pt; text-align: left;"> $[***] </td>
                  </tr>
                  <tr>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(255, 255, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0);">
                      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">[***]</font></font></div>
                    </td>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(255, 255, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0);">
                      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">$[***]</font></font></div>
                    </td>
                  </tr>
                  <tr>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                      [***] </td>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(204, 238, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); font-family: &quot;Times New
                      Roman&quot;; font-size: 10pt; text-align: left;"> $[***] </td>
                  </tr>
                  <tr>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(255, 255, 255); border-top: 2px solid rgb(0, 0, 0); border-left: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); font-family: &quot;Times New
                      Roman&quot;; font-size: 10pt; text-align: left;"> [***] </td>
                    <td style="width: 45%; vertical-align: middle; background-color: rgb(255, 255, 255); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                      <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">$[***]</font></font></div>
                    </td>
                  </tr>

              </table>
            </div>
            <div style="text-align: justify;">
              <div>
                <div> <br>
                </div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z64131d4eb1e54f9c82efceda0ecff5b0">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Non-ALS Collaboration Program Milestone Payments for Achievement of
                                Pre-Licensing Milestone Events</u></font>. As further consideration for Biogen&#8217;s Options, on a Collaboration Program-by-Collaboration Program basis where such a Collaboration Program is not an ALS Collaboration Program,
                            Biogen will pay to Ionis the milestone payments as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 1</u></font> below when a milestone event (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Standard Pre-Licensing Milestone Event</font>&#8221;) listed in <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-variant: small-caps;"><u>Table 1</u></font> is first achieved by a Collaboration Product under such Collaboration Program:</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
                <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
                  <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">74</font></div>
                  <div id="DSPFPageBreak" 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>
              </div>
            </div>
            <table cellspacing="0" cellpadding="2" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse;" id="z0abb2635cd3b455e99e19d555d1cfe9f">

                <tr>
                  <td colspan="3" style="vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div style="text-align: center; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Table 1</u></font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Standard Pre-Licensing </font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Milestone Event</font></div>
                  </td>
                  <td style="width: 34%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Milestone Event Payment per </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Collaboration Program that is not </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">an ALS Collaboration Program </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">or Biogen Conducted Non-ALS</font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> Collaboration Program</font></font></div>
                  </td>
                  <td style="width: 33%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Milestone Event Payment per </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Biogen Conducted Non-ALS</font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> Collaboration Program</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> [***]
                  </td>
                  <td style="width: 34%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">[***]</font></font></div>
                  </td>
                  <td style="width: 34%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">[***]</font></font></div>
                  </td>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">$[***]</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> [***]
                  </td>
                  <td style="width: 34%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> [***]
                  </td>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                </tr>

            </table>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">On a Collaboration
                  Program-by-Collaboration Program basis, where such a Collaboration Program is not an ALS Collaboration Program, Biogen will pay to Ionis the Milestone Event payments as set forth in </font><font style="font-size: 10pt; font-family:
                  'Times New Roman'; font-variant: small-caps;"><u>Table 1</u></font><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> after the applicable Milestone Event is first achieved by a Collaboration
                  Product under such Collaboration Program, even if Biogen has exercised the applicable Option prior to achievement of the Milestone Event; </font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided,
                  however</font>, that if Biogen exercises the Option prior to achievement of the [***] Milestone Event, then the milestone payment for achievement of the [***]<font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New
                  Roman';"> Milestone Event will be reduced to $[***].</font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zba220ebd26e340d081d139386b8bd5e7">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>ALS Collaboration Program Milestone Payments for Achievement of Pre-Licensing
                                Milestone Events</u></font>. As further consideration for Biogen&#8217;s Options, on an ALS Collaboration Program-by-ALS Collaboration Program basis, Biogen will pay to Ionis the milestone payments as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 2</u></font> below when a milestone event (each, an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                              font-style: italic;">ALS Pre-Licensing Milestone Event</font>&#8221;) listed in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 2</u></font> is first achieved by a Collaboration
                            Product under such a Collaboration Program. Subject to the penultimate paragraph of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.7</u></font>, the amount of the payment for such Milestone Events
                            will be determined based on whether or not such ALS Collaboration Program is a [***] Collaboration Program:</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <table cellspacing="0" cellpadding="2" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse;" id="z026fc57ef18f48dabe06a83e97d9c4b8">

                <tr>
                  <td colspan="4" style="width: 100%; vertical-align: middle; border-left: #000000 2px solid; border-right: #000000 2px solid; border-top: #000000 2px solid; border-bottom: #000000 2px solid;">
                    <div style="text-align: center; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Table 2</u></font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 23.68%; vertical-align: middle; border-left: #000000 2px solid; border-right: #000000 2px solid; border-top: #000000 2px solid; border-bottom: #000000 2px solid;">
                    <div>&#160;</div>
                    <div>&#160;</div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ALS Pre-Licensing </font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Milestone Event</font></div>
                  </td>
                  <td style="width: 26.32%; vertical-align: middle; border-left: #000000 2px solid; border-right: #000000 2px solid; border-top: #000000 2px solid; border-bottom: #000000 2px solid;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Column 1</u></font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Milestone Event </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Payment per ALS </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Collaboration Program</font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> that is </font><font style="font-size: 10pt;
                          font-family: 'Times New Roman'; font-style: italic;"><u>not</u></font><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> a [***] </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Collaboration Program </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">[***]</font></font></div>
                  </td>
                  <td style="width: 25.38%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-top: #000000 2px solid; border-bottom: #000000 2px solid;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Column 2</u></font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Milestone Event</font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> Payment per [***] </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Collaboration Program</font></font></div>
                  </td>
                  <td style="width: 24.62%; vertical-align: top; border-left: #000000 2px solid; border-right: #000000 2px solid; border-top: #000000 2px solid; border-bottom: #000000 2px solid;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Column 3</u></font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Milestone Event </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Payment for the [***]</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 23.68%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    [***] </td>
                  <td style="width: 26.32%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    $[***] </td>
                  <td style="width: 25.38%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    $[***] </td>
                  <td style="width: 24.62%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    [***] </td>
                </tr>
                <tr>
                  <td style="width: 23.68%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    [***] </td>
                  <td style="width: 26.32%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    $[***] </td>
                  <td style="width: 25.38%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    $[***] </td>
                  <td style="width: 24.62%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    [***] </td>
                </tr>
                <tr>
                  <td style="width: 23.68%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    [***] </td>
                  <td style="width: 26.32%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    $[***] </td>
                  <td style="width: 25.38%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    $[***] </td>
                  <td style="width: 24.62%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    [***] </td>
                </tr>
                <tr>
                  <td style="width: 23.68%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    [***] </td>
                  <td style="width: 26.32%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    [***] </td>
                  <td style="width: 25.38%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    [***] </td>
                  <td style="width: 24.62%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    $[***] </td>
                </tr>
                <tr>
                  <td style="width: 23.68%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    [***] </td>
                  <td style="width: 26.32%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    $[***] </td>
                  <td style="width: 25.38%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    $[***] </td>
                  <td style="width: 24.62%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                    $[***] </td>
                </tr>

            </table>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">75</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">On an ALS Collaboration Program-by-ALS Collaboration Program basis, Biogen will pay to Ionis the Milestone Event payments as set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 2</u></font> after the applicable Milestone Event is first achieved by a Collaboration Product under such an ALS Collaboration
                Program, even if Biogen has exercised the applicable Option prior to achievement of the Milestone Event.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdf5e6374f37142b5bc9b474668a12e3b">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>License Fee</u></font>. On an Option-by-Option basis, together with Biogen&#8217;s
                            written notice to Ionis stating that Biogen is exercising such Option in accordance with this Agreement, Biogen will pay to Ionis a license fee of (A) $[***] for any Collaboration Program [***]; <font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that if (i) Biogen exercises the Option prior to the [***], the license fee for such Option will be [***] or (ii) Biogen exercises the Option to a
                            [***] Collaboration Program, subject to the last paragraph of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.7</u></font>, the license fee for such Option will be [***], or (B) $[***]; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that if Biogen exercises the Option prior to the [***], the license fee for such Option will be [***]. If Biogen notifies
                            Ionis that it desires to exercise an Option prior to the [***], then the Parties will discuss and negotiate in good faith.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd7f58f798dc24fa3aea023384e904c17">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Milestone Payments for Achievement of Post-Licensing Milestone Events</u></font>.
                            On a Collaboration Program-by-Collaboration Program basis, Biogen will pay to Ionis the milestone payments as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 3</u></font>
                            below when a milestone event (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Post-Licensing Milestone Event</font>&#8221;) listed in <font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 3</u></font> is first achieved by a Collaboration Product under such Collaboration Program, where (subject to the last paragraph of <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>Section 6.7</u></font>) the amount of the payment for such Milestone Event will be determined based on whether or not such Collaboration Program is a [***] Collaboration Program:</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <table cellspacing="0" cellpadding="2" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse;" id="zf680a2a878d944babaa03b0aa0f95bea">

                <tr>
                  <td colspan="3" style="vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div style="text-align: center; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Table 3</u></font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div>&#160;</div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Post-Licensing Milestone </font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Event</font></div>
                  </td>
                  <td style="width: 34%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); text-align: left;">
                    <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Column 1</u></font></font></div>
                    <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Milestone Event Payment per</font></font></div>
                    <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;"> Collaboration Program that is </font></font></div>
                    <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;"><u>not</u></font><font style="background-color: rgb(255, 255,
                          255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;"> a [***] Collaboration</font></font></div>
                    <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;"> Program</font></font></div>
                  </td>
                  <td style="width: 33%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Column 2</u></font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
                          </u></font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Milestone Event Payment</font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> per [***] Collaboration </font></font></div>
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Program</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> [***]
                  </td>
                  <td style="width: 34%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> [***]
                  </td>
                  <td style="width: 34%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> [***]
                  </td>
                  <td style="width: 34%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> [***]
                  </td>
                  <td style="width: 34%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                  <td style="width: 33%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;"> $[***]
                  </td>
                </tr>

            </table>
            <div> <br>
            </div>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">On a Collaboration Program-by-Collaboration Program basis, if Biogen exercises an Option for a Collaboration Program that is <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>not</u></font> a [***] Collaboration Program, prior to the [***], Biogen will pay to Ionis [***] upon the earlier of (a) [***] or (b) [***]. For the avoidance of doubt, if such
                $[***] payment is paid pursuant to clause (b) of the preceding sentence, such payment will be in addition to the amount due upon the occurrence of the corresponding Post-Licensing Milestone Event under <font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 3</u></font> above.</font></div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">76</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">If, with respect to a particular [***] Collaboration Program, Biogen Initiates a Phase 2 Trial in an indication other than [***]
                (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>, [***] or a [***] indication) Biogen will pay Ionis [***] within [***] days of the Initiation of such Phase 2 Trial.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">If, with respect to a particular [***] Collaboration Program, Biogen Initiates a Phase 3 Trial or files for Approval in an
                indication other than [***] (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>, [***] or a [***] indication) such Collaboration Program will thereafter be a Collaboration Program (and not a [***]
                Collaboration Program) under this Agreement, and Biogen will pay Ionis (i) $[***] and (ii) [***] within [***] days of the Initiation of such Phase 3 Trial or filing for Approval.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd18064d155624f74ae539e9ed5f480ee">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.8.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Limitations on Milestone Payments; Exceptions; Notice</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z474ea3edae024cd19174413d5550ae13">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.8.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">On a Collaboration Product-by-Collaboration Product basis, the [***] milestone payment in <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-variant: small-caps;"><u>Table 3</u></font> is creditable against the first Milestone Event payment for [***]. For example, if the [***] Milestone Event is achieved by a Collaboration Product in the United States, then
                            the milestone payment for such Milestone Event is creditable against the first to occur of the (i) [***] (ii) [***] or (iii) [***] milestone payments for such Collaboration Product.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc97314162a154cfe8f664a3dd4f749f0">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.8.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">On a Biogen Alternate Modality Target-by-Biogen Alternate Modality Target basis, each milestone payment set forth in <font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-variant: small-caps;"><u>Table X</u></font> above will be paid only once upon the first achievement of the Milestone Event regardless of how many Biogen Alternate Modality Products related to such
                            Biogen Alternate Modality Target achieve such Milestone Event.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z721ff974a4ca4cbc8d924249fd75e771">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.8.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">On a Collaboration Program-by-Collaboration Program basis, each milestone payment set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-variant: small-caps;"><u>Table 1,</u></font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 2</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-variant: small-caps;">&#160;</font>and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 3</u></font> above will be paid only once upon the first achievement of the Milestone
                            Event regardless of how many Collaboration Products under such Collaboration Program achieve such Milestone Event.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zffd3a3b509ac4e4fb8b14438046836b5">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.8.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 [***] without
                            achieving the [***] then upon achieving the [***] Milestone Event, both the [***] and [***] Milestone Event payments are due. Similarly, if a Party proceeds directly to [***] without achieving the [***] then upon achieving the
                            [***] Milestone Event, both the [***] and [***] Milestone Event payments are due. If Biogen [***] for a Biogen Alternate Modality Product, then both the [***] milestone payment and the [***] milestone payment will be due upon
                            [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">77</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z21fcffde6e10443ea2115e0cd703900b">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.8.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Each time a Milestone Event is achieved under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font>, Biogen will send Ionis,
                            or Ionis will send Biogen, as the case may be, a written notice thereof promptly (but no later than five Business Days) following the date of achievement of such Milestone Event and such payment will be due within [***] days of
                            the date such notice was delivered.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2ff480469a0d4ff989df1c5bdbf19192">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.8.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">With respect to the [***] Collaboration Program for [***], except as expressly set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section








                                6.5</u></font>, the milestone payments and license fees set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.5</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                                6.6</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.7</u></font> for [***] Collaboration Programs that are not [***] Collaboration Programs shall apply with respect to such [***]
                            Collaboration Program.&#160; For clarity, the provisions of the Neurology Drug Discovery and Development Collaboration, Option and License Agreement between Ionis and Biogen, dated as of December 10, 2012, as such agreement may be
                            amended from time to time, shall not apply with respect to the [***] Collaboration Program for [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6fc3612c3a224bafbd45e5b3d3c7b369">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.9.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Royalty Payments to Ionis for Biogen Alternate Modality Products</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze7eb6af6bbb8427eb958e31f6daa4ef9">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.9.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Royalties for Biogen Alternate Modality Products</u></font>. As partial
                            consideration for the rights granted to Biogen hereunder, subject to the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.3(b)</u></font> and <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 6.9.2</u></font>, Biogen will pay to Ionis a [***]% royalty on Annual worldwide Net Sales of Biogen Alternate Modality Products sold by Biogen, its Affiliates or Sublicensees, on a
                            country-by-country basis (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Alternate Modality Royalty</font>&#8221;).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9269a3d55f1a4a1792ec2debf436f008">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.9.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Royalty Period for Biogen Alternate Modality Products</u></font>. Biogen&#8217;s
                            obligation to pay Ionis the Biogen Alternate Modality Royalty above with respect to a Biogen Alternate Modality Product will continue on a country-by-country and Biogen Alternate Modality Product-by-Biogen Alternate Modality
                            Product basis from the date of First Commercial Sale of such Biogen Alternate Modality Product until the [***] anniversary of the First Commercial Sale of such Biogen Alternate Modality Product in such country (such royalty
                            period, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Alternate Modality Royalty Period</font>&#8221;); <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-style: italic;">provided</font>,<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#160;</font>that Biogen will pay [***] (if applicable) for as long as Biogen, its Affiliates or Sublicensees
                            are selling Biogen Alternate Modality Products.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">78</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za0fbe077a76c4c5cb8fdfd08ad2c1238">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen will pay Ionis royalties on Net Sales of Biogen Alternate Modality Products arising from named patient and other similar programs under Applicable Laws, and
                            Biogen will provide reports and payments to Ionis consistent with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.14</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc4a9da6fdcd549b08787ebb266ac191b">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">No royalties are due on Net Sales of Biogen Alternate Modality Products arising from compassionate use and other programs providing for the delivery of Biogen
                            Alternate Modality Product at no cost.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zda3ce94183b343aea51199615b99a475">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The sales of Biogen Alternate Modality Products arising from named patient, compassionate use, or other similar programs will not be considered a First Commercial
                            Sale for purposes of calculating the Biogen Alternate Modality Royalty Period.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4b8518ef81164b7ea52e3377aa7bf66b">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.10.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Royalty Payments to Ionis for Collaboration Products</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0c9906ba94bb4e85b2e211a210658db0">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.10.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen Full Royalty for Collaboration Products</u></font>. As partial
                            consideration for the rights granted to Biogen hereunder, subject to the provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.1</u></font> and <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 6.10.2</u></font>, Biogen will pay to Ionis royalties on a Collaboration Program-by-Collaboration Program basis, on Annual worldwide Net Sales of Collaboration Products included in
                            the applicable Collaboration Program sold by Biogen, its Affiliates or Sublicensees, on a country-by-country basis, in each case in the amounts as follows in <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-variant: small-caps;"><u>Table 4</u></font> below (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Full Royalty</font>&#8221;):</font></div>
                      </td>
                    </tr>

                </table>
                <div style="text-align: justify;">
                  <div><br>
                  </div>
                  <div>
                    <div>
                      <table cellspacing="0" cellpadding="2" border="0" style="border-collapse: collapse; width: 80%; font-family: &quot;Times New Roman&quot;; font-size: 10pt; margin-left: 72pt;" id="z2843e4b538fa4b9791b29ceaff9544f0">

                          <tr>
                            <td colspan="3" style="vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                              <div style="text-align: center;"><font style="font-weight: bold; font-variant: small-caps; font-family: 'Times New Roman'; font-size: 10pt;"><u>Table 4</u></font></div>
                            </td>
                          </tr>
                          <tr>
                            <td style="width: 15%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Royalty</font></div>
                              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Tier</font></div>
                            </td>
                            <td style="width: 49%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Annual Worldwide Net Sales of Collaboration </font></div>
                              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Products for the applicable Collaboration </font></div>
                              <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Program</font></div>
                            </td>
                            <td style="width: 16%; vertical-align: middle; border-left: #000000 2px solid; border-right: #000000 2px solid; border-top: #000000 2px solid; border-bottom: #000000 2px solid;">
                              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Royalty</font></div>
                              <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Rate</font></div>
                            </td>
                          </tr>
                          <tr>
                            <td style="width: 15%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align:
                              center;"> 1 </td>
                            <td style="width: 49%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                              For the portion of Annual Worldwide Net Sales&#160; &lt; $[***] </td>
                            <td style="width: 16%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                              [***]% </td>
                          </tr>
                          <tr>
                            <td style="width: 15%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align:
                              center;"> 2 </td>
                            <td style="width: 49%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                              For the portion of Annual Worldwide Net Sales&#160; <u>&gt;</u> $[***] but &lt; $[***] </td>
                            <td style="width: 16%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                              [***]% </td>
                          </tr>
                          <tr>
                            <td style="width: 15%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align:
                              center;"> 3 </td>
                            <td style="width: 49%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                              For the portion of Annual Worldwide Net Sales&#160; <u>&gt;</u> $[***] but &lt; $[***] </td>
                            <td style="width: 16%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                              [***]% </td>
                          </tr>
                          <tr>
                            <td style="width: 15%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align:
                              center;"> 4 </td>
                            <td style="width: 49%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                              For the portion of Annual Worldwide Net Sales&#160; <u>&gt;</u> $[***] </td>
                            <td style="width: 16%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255); font-family: &quot;Times New Roman&quot;; font-size: 10pt; text-align: left;">
                              [***]% </td>
                          </tr>

                      </table>
                      <div> <br>
                      </div>
                    </div>
                  </div>
                  <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
                    <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">79</font></div>
                    <div id="DSPFPageBreak" 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>
                </div>
              </div>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Annual worldwide Net Sales of Collaboration Products will be calculated by [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbaac58dc864d48659191c87ae86aa5f3">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen will pay Ionis royalties on Net Sales of Collaboration Products arising from named patient and other similar programs under Applicable Laws, and Biogen will
                            provide reports and payments to Ionis consistent with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.14</u></font>. No royalties are due on Net Sales of Collaboration Products arising from
                            compassionate use and other programs providing for the delivery of Collaboration Product at no cost. The sales of Collaboration Products arising from named patient, compassionate use, or other similar programs will not be
                            considered a First Commercial Sale for purposes of calculating the Full Royalty Period.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3cc46a63d44f4115ac157dd20b573c7e">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">For purposes of clarification, any Ionis Product-Specific Patents assigned to Biogen as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section












                                4.2.1</u></font> will still be considered Ionis Product-Specific Patents for determining the royalty term and applicable royalty rates under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z447a08b9734147db8697912dc4f7bc11">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">For clarity, the provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10</u></font> shall apply to Net Sales of
                            Collaboration Products under the [***] Collaboration Program for [***], and the provisions of the Neurology Drug Discovery and Development Collaboration, Option and License Agreement between Ionis and Biogen, dated as of
                            December 10, 2012, as such agreement may be amended from time to time, shall not apply.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z54b9370973664fd483d8c7b8d4fdc65c">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.10.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Application of Royalty Rates for Collaboration Products</u></font>. All
                            royalties set forth under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.1</u></font> are subject to the provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                                6.10.2</u></font>, and are payable as follows:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0ce1488722eb454ab7cac10f8026d90c">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Full Royalty Period for Collaboration Products</u></font>. Biogen&#8217;s obligation
                            to pay Ionis the Biogen Full Royalty above with respect to a Collaboration Product will continue on a country-by-country and Collaboration Product-by-Collaboration Product basis from the date of First Commercial Sale of such
                            Collaboration Product until the later of the date of expiration of (i) the last Valid Claim within the Licensed Patents Covering such Collaboration Product in the country in which such Collaboration Product is made, used or
                            sold, (ii) the data exclusivity period conferred by the applicable Regulatory Authority in such country with respect to such Collaboration Product (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>,
                            such as in the case of an orphan drug), or (iii) the [***] anniversary of the First Commercial Sale of such Collaboration Product in such country (such royalty period, the &#8220;<font style="font-size: 10pt; font-family: 'Times New
                              Roman'; font-weight: bold; font-style: italic;">Full Royalty Period</font>&#8221;).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">80</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za2afb7c3b87d4a6da085d9298069e278">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Competition from Generic Products for Collaboration Products</u></font>.
                            Subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.11</u></font>, on a country-by-country and Collaboration Product-by-Collaboration Product basis, if, within the [***], a Generic Product is
                            sold in a country, then the Biogen Full Royalty rate used to pay Ionis royalties on such Collaboration Product in such country will be reduced to [***]% of the otherwise applicable Biogen Full Royalty rate. For the purpose of
                            determining the [***] for a particular Collaboration Product under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.2(b)</u></font>, if requested by Biogen, Ionis and Biogen will meet and
                            confer and mutually agree upon the Parties&#8217; best estimate of when the Full Royalty Period [***] in each country where Collaboration Products are being sold.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zacb3f47abdf44cd7903f880fef8e3154">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Reduced Royalty Period for Collaboration Products</u></font>. Subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.11</u></font>, on a country-by-country and Collaboration Product-by-Collaboration Product basis, after the expiration of the Full Royalty Period and until
                            the end of the Reduced Royalty Period, in lieu of the royalty rates set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 4</u></font> of <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 6.10.1</u></font>, Biogen will pay Ionis royalty rates (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Reduced
                              Royalty</font>&#8221;) on Net Sales of Collaboration Products calculated on a Calendar Year-by-Calendar Year basis by <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>[***]</u></font>; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that the Biogen Reduced Royalty rate in each country will in no event exceed the [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z11ba0985143c4667a0b8fb6a69b4e43a">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>End of Royalty Obligation for Collaboration Products</u></font>. On a
                            country-by-country and Collaboration Product-by-Collaboration Product basis, other than [***], Biogen&#8217;s obligation to make royalty payments hereunder for such Collaboration Product in such country will end on the expiration of
                            the Reduced Royalty Period in such country. &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 [***] for such Collaboration Product in such country and ending when the [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4780e773444d484db40ca923855ae292">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Royalty Examples</u></font>. <font style="font-size: 10pt; font-family: 'Times
                              New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.10.2(e)</u></font> attached hereto contains examples of how royalties will be calculated under
                            this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z043570967dcf4f52add235f8eb6af54a">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Allocation of Net Sales</u></font>. If, by reason of one or more royalty rate
                            adjustments under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.2</u></font>, different royalty rates apply to Net Sales of Collaboration Products from different countries, Biogen will
                            [***] such Net Sales [***]. <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.10.2(f)</u></font>
                            attached hereto contains examples of how Net Sales of Collaboration Products from different countries at different royalty rates will be [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">81</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdf63bb3daf76453a990a93405757bf62">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.11.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Limitation on Aggregate Reduction for Royalties for Collaboration Products</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zea90313925f24ac086974e5e3137768e">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.11.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In no event will the aggregate royalty reductions under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.2(b)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.2(c)</u></font> reduce the royalties payable to Ionis on Net Sales of a Collaboration Product in any given period to an amount that is less than the
                            [***] for such Collaboration Product.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdf469d5ef54643d49c1545f5615f8261">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.11.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In no event will the aggregate royalty offsets under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(b)</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(d)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>7.1.3(c)</u></font> reduce the royalties payable to Ionis on Net Sales of a Collaboration Product in any given period to an amount that is less than the greater of [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For example, if the Royalty Quotient during a given Calendar Year in the Reduced Royalty Period is less than [***]%, then the
                offsets under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(b)</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(d)</u></font> and <font style="font-size:
                  10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.1.3(c)</u></font> will not apply during such Calendar Year but the full Royalty Quotient reduction pursuant
                to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.2(c)</u></font> will apply.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">As an additional example, if the Royalty Quotient during a given Calendar Year in the Reduced Royalty Period is [***]%, and the
                [***] in such Calendar Year are [***]% of the applicable royalty rates in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 4</u></font> of <font style="font-size: 10pt; font-family: 'Times
                  New Roman';"><u>Section 6.10.1</u></font>, then Biogen may apply the offsets under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(b)</u></font>, <font style="font-size: 10pt; font-family: 'Times New
                  Roman';"><u>Section 6.13.3(d)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.1.3(c)</u></font> until the actual
                royalty payment made to Ionis in such Calendar Year is equal to [***]% of the applicable royalty rates in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Table 4</u></font> of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc8bf49f2a27549d297a91f2908d86429">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.12.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Reverse Royalty Payments to Biogen for a Discontinued Collaboration Product</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9b9f3bc0b25546e8a8d0fa9b9c373ca3">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.12.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Reverse Royalty for a Discontinued Collaboration Product</u></font>. If Ionis
                            or any of its Affiliates or Sublicensees Commercializes a Discontinued Collaboration Product for which Biogen has paid Ionis the license fee under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.5</u></font>,
                            then following the First Commercial Sale of such Discontinued Collaboration Product by Ionis or its Affiliates or Sublicensees, Ionis will pay Biogen or its designated Affiliate a royalty of [***]% of Annual worldwide Net Sales
                            of such Discontinued Collaboration Product (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Reverse</font><font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-weight: bold;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Royalties</font>&#8221;). Ionis&#8217; obligation to pay Biogen Reverse Royalties will [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3a9715080263462285e84845241acfd2">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.12.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Applicable Royalty Provisions</u></font>. In addition to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.12</u></font>, the definition of Net Sales in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 1</u></font>
                            and the other provisions contained in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font> governing payment of royalties from Biogen to Ionis will govern the payment of Reverse Royalties
                            from Ionis to Biogen under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.12</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">mutatis mutandis</font>,
                            including the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections 6.10.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.13</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.14</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.15</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.16</u></font>,
                            and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.17</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">82</font></div>
              <div id="DSPFPageBreak" style="page-break-after: always;">
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zad9db8f0a0d44709b031084ab8e64e50">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.13.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Third Party Payment Obligations</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb78db29da56e4abeac67d3e48a42b770">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.13.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Existing Ionis In-License Agreements</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc526767c754b4888a044b9abdee71b37">

                    <tr>
                      <td style="width: 81.35pt;"><br>
                      </td>
                      <td style="width: 35.65pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Certain of the Licensed Technology Controlled by Ionis as of the Effective Date licensed to Biogen under <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> were in-licensed or were acquired by Ionis under the agreements with Third Party
                            licensors or sellers listed on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 6.13.1</u></font>
                            or in a separate written agreement between the Parties (all such license or purchase agreements being the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis In-License
                              Agreements</font>&#8221;), and certain milestone or royalty payments and license maintenance fees may become payable by Ionis to such Third Parties under the Ionis In-License Agreements based on the Development and Commercialization
                            of a Product by Biogen under this Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7b830c48d8094f77bcbd678e8279172a">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Any payment obligations arising under the Ionis In-License Agreements as existing on the Effective Date as they apply to Collaboration Products for High Interest
                            Targets designated as of the Effective Date, will be paid by [***] as [***].&#160; </font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5ee28982fbbd4b8692656ebc37beb8c4">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.13.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>New In-Licensed Ionis Product-Specific Patents; Ionis Manufacturing and
                                Analytical Patents</u></font>.<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>If after the Effective Date, Ionis obtains Third Party Patent Rights necessary or useful to Develop,
                            Manufacture or Commercialize a Product that would have been considered an Ionis Product-Specific Patent had Ionis Controlled such Patent Rights on the Effective Date, to the extent Controlled by Ionis, Ionis will include such
                            Third Party Patent Rights in the license granted to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                                4.1.1(b)</u></font> (as applicable) if Biogen agrees in writing to pay Ionis as [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2edacdae789740c6bb8e507ca346ed31">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.13.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Additional Core IP In-License Agreements</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z180bf3051e3c45acb1c2f7a255f45579">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen will promptly provide Ionis written notice of any Additional Core IP Biogen believes it has identified and Ionis 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. If Ionis obtains such a Third Party license, Ionis will include such Additional Core IP in the license granted to
                            Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font>, and any financial obligations under such Third Party agreement will be paid solely by [***] as [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">83</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8f4fe6cbe3ff4b42b2cdd7b5b8bdca07">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, however, Ionis elects not to obtain such a license to such Third Party intellectual property, Ionis will so notify Biogen, and Biogen may obtain such a Third
                            Party license and, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.11.2</u></font>, Biogen may offset an amount equal to [***]% of any [***] paid by Biogen under such Third Party license
                            against any [***] of this Agreement in such country for [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za46f6ee1e09b4c4da8186f44b04b7668">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If it is unclear whether certain intellectual property identified by Biogen pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                                6.13.3(a)</u></font> is Additional Core IP under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(b)</u></font>, Ionis will send written notice to such effect to Biogen, and the Parties will
                            engage a mutually agreed upon independent Third Party intellectual property lawyer with expertise in the patenting of Oligonucleotides, 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 Biogen is permitted to [***]. The costs of any Third Party expert engaged under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(c)</u></font> will be paid by the Party
                            against whose position the Third Party lawyer&#8217;s determination is made.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb5286edfbfdb401c9ee78c6730561d18">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Notwithstanding the determination of the Third Party lawyer under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(c)</u></font>,
                            if a Third Party Controlling Additional Core IP is awarded a judgment from a court of competent jurisdiction arising from its claim against Biogen asserting that [***], Biogen will be permitted to [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1c92439cb49144798e33befbfa327156">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.13.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Other Third Party Payments</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf19e1e851592470e94ffc765bf16958a">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Third Party Agreements</u></font>. Except as otherwise expressly agreed
                            to by Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.2</u></font>, after Biogen is granted the license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section








                                4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> for a particular Product, Biogen will be responsible for paying [***]% of the [***] arising under any
                            Third Party agreements entered into by Ionis where either [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1be11d4af2354c55b3606d25e20fbbfb">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen&#8217;s Third Party Agreements</u></font>. Without limiting any applicable
                            [***] under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(b)</u></font>, Biogen will be responsible for paying [***]% of the [***] arising under any Third Party agreements entered into by
                            Biogen as they apply to Products.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z04750483b7b44fc2b15d2af87e0b059b">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.14.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Payments</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">84</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zcc85255d43874264a70fc583d851f8fb">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.14.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Commencement</u></font>. Beginning with the Calendar Quarter in which the First
                            Commercial Sale for a Product is made and for each Calendar Quarter thereafter, Biogen will make royalty payments to Ionis under this Agreement within [***] following the end of each such Calendar Quarter. Each royalty payment
                            will be accompanied by a report, summarizing Net Sales for Products during the relevant Calendar Quarter and the calculation of royalties due thereon, including country, units, sales price, the exchange rate used and the type of
                            Product (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font>, whether it is a Collaboration Product or Biogen Alternate Modality Product) and the aggregate reduction to gross sales to arrive at Net
                            Sales. Following the end of the first full Calendar Quarter subsequent to First Commercial Sale in a Major Market of any Product (but not in any subsequent Calendar Quarter unless there is a material change in the amount of any
                            reduction to gross sales or the methodology used by Biogen to calculate any such reduction), Biogen will also include in such report a description of the reductions to gross sales to arrive at Net Sales, broken down by each
                            category of reduction listed in clauses (a) through (d) of the definition of &#8220;Net Sales&#8221; and a non-binding qualitative analysis describing how Biogen anticipates such reductions may fluctuate over time. If no royalties are
                            payable in respect of a given Calendar Quarter, Biogen will submit a written royalty report to Ionis 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 is made and for each Calendar Quarter thereafter, within [***] following the end of each such Calendar Quarter, Biogen will provide Ionis a [***] report estimating the
                            total Net Sales of, and royalties payable to Ionis for Products projected for such Calendar Quarter.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z65398f95aa0345b999a58777012bc37b">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.14.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Mode of Payment</u></font>. 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 Ionis in writing, and (iii) non-creditable [***],
                            irrevocable and non-refundable. Whenever for the purposes of calculating the royalties payable under this Agreement conversion from any foreign currency will be required, all amounts will first be calculated in the currency of
                            sale and then converted into United States dollars by applying the monthly average rate of exchange calculated by using the foreign exchange rates published in Bloomberg during the applicable month starting two Business Days
                            before the beginning of such month and ending two Business Days before the end of such month as utilized by Biogen, in accordance with generally accepted accounting principles, fairly applied and as employed on a consistent
                            basis throughout Biogen&#8217;s operations.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf32dbe6734af457d81424fe263023e1a">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.14.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Records Retention</u></font>. Commencing with the First Commercial Sale of a
                            Product, Biogen will keep complete and accurate records pertaining to the sale of Products for a period of [***] after the year in which such sales occurred, and in sufficient detail to permit Ionis to confirm the accuracy of
                            the Net Sales or royalties paid by Biogen hereunder.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">85</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdda30b46780f4da6b4eb71453178bfad">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.14.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>No Payments for non-ASOs for Pre-Existing Targets</u></font>.&#160; For the
                            avoidance of doubt, in no event shall any payments be due to Ionis under this Agreement with respect to any non-Oligonucleotide product developed or commercialized for a Pre-Existing Target.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfbf4c271efee4d4ca0750196a6d7b4f9">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.15.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Audits</u></font>. After Biogen is granted the license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> for a particular Product, during the
                            Agreement Term and for a period of [***] thereafter, at the request and expense of Ionis, Biogen will permit an independent certified public accountant of nationally recognized standing appointed by Ionis, at reasonable times
                            and upon reasonable notice, but in no case more than [***], 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 [***]. As a condition to examining any records of Biogen, such auditor will sign a nondisclosure agreement reasonably acceptable to Biogen in form and substance. Any and
                            all records of Biogen examined by such independent certified public accountant will be deemed Biogen&#8217;s Confidential Information. Upon completion of the audit, the accounting firm will provide both Biogen and Ionis with a written
                            report disclosing whether the royalty payments made by Biogen are correct or incorrect and the specific details concerning any discrepancies (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                              font-style: italic;">Audit Report</font>&#8221;). If, as a result of any inspection of the books and records of Biogen, it is shown that Biogen&#8217;s payments under this Agreement were less than the royalty amount which should have been
                            paid, then Biogen will make all payments required to be made by paying Ionis the difference between such amounts to eliminate any discrepancy revealed by said inspection within [***] days of receiving the Audit Report, with
                            interest calculated in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.17</u></font>. If, as a result of any inspection of the books and records of Biogen, it is shown that Biogen&#8217;s
                            payments under this Agreement were greater than the royalty amount which should have been paid, then [***]; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that if
                            [***]. Ionis will pay for such audit, except that if Biogen is found to have underpaid Ionis by more than [***]% of the amount that should have been paid, Biogen will reimburse Ionis&#8217; reasonable costs of the audit.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9f0b4eb7ae7b4e82b02a97210494de17">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.16.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Taxes</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb546dc06f0054515be361269cc040b2a">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.16.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Taxes on Income</u></font>. 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5d96923272f2407dac3c4925dacd7f23">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.16.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Withholding Tax</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1ee1041c719249e38b26c3fed77334d1">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Parties agree to cooperate with one another and use reasonable efforts to lawfully avoid or reduce tax withholding or similar obligations in respect of
                            royalties, milestone payments, and other payments made by the paying Party to the receiving Party under this Agreement. To the extent the paying Party is required to deduct and withhold taxes, interest or penalties on any
                            payment, the paying Party will pay the amounts of such taxes to the proper governmental authority for the account of the receiving Party and remit the net amount to the receiving Party in a timely manner. The paying Party will
                            promptly furnish the receiving Party with proof of payment of such taxes. If documentation is necessary in order to secure an exemption from, or a reduction in, any withholding taxes, the Parties will provide such documentation
                            to the extent they are entitled to do so.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">86</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zeb982016606145ed9b08c7ae6376e4cf">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">With respect to any commercial supply agreement entered between the Parties for the commercial supply of API under this Agreement, such supply agreement will (i)
                            provide that only Biogen will claim any tax benefit allowed under IRC Section 199 Income Attributable to Domestic Production Activities, and (ii) include compensation to Ionis reflecting the value of the reasonably anticipated
                            tax benefit under IRC Section 199 Income Attributable to Domestic Production Activities forfeited by Ionis.&#160; If the IRS determines that Biogen is not entitled to the tax benefits under Section 199, Ionis is not required to
                            reimburse Biogen for this tax benefit unless Ionis receives a cash benefit on its federal tax return.&#160;&#160; A cash benefit will include any utilization of net operating losses that were generated in a year in which Ionis claimed any
                            IRC Sec 199 deduction.&#160; The reimbursement to Biogen would be an amount equal to the Section 199 deduction times thirty-five percent, less any administrative costs to compute the tax benefit.&#160; The reimbursement would be due to
                            Biogen within 90 days after filing any original or amended federal tax return.&#160; If the IRS determines that Ionis is not eligible for the tax benefit or determines the tax benefit should be a different amount, Biogen will pay
                            back to Ionis the amount of any adjustment.&#160; Ionis will notify Biogen within 30 days of filing a return that claims such deduction or utilizes a related net operating loss.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z839dc320b8fc47d89560c51c8c07e05e">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.16.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Tax Cooperation</u></font>. Ionis will provide Biogen with any and all tax
                            forms that may be reasonably necessary in order for Biogen to lawfully not withhold tax or to withhold tax at a reduced rate under an applicable bilateral income tax treaty. Following Biogen&#8217;s timely receipt of such tax forms
                            from Ionis, Biogen 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.&#160; Ionis will provide any such tax forms to Biogen upon
                            request and in advance of the due date. Each Party will provide the other with reasonable assistance to determine if any taxes are applicable to payments under this Agreement and 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.16</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">87</font></div>
              <div id="DSPFPageBreak" 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>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.16</u></font> are to be read
                in conjunction with the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.4</u></font> below.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd9f070eb05844ae9a9a38d1b8e1aad6a">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">6.17.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Interest</u></font>. 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) the rate announced by Bank of America (or its successor) as its prime rate in effect on the
                            date that such payment would have been first due plus 1% or (ii) the maximum rate permissible under Applicable Law.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 7.</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">INTELLECTUAL PROPERTY</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze006cc0941ca4427868a91d002f9cc5d">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ownership</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za273e5b0b6124a5aba31a2f7ae598bbb">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis Technology and Biogen Technology</u></font>. As between the Parties,
                            Ionis will own and retain all of its rights, title and interests in and to the Licensed Know-How and Licensed Patents and Biogen will own and retain all of its rights, title and interests in and to the Biogen Know-How and Biogen
                            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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd61b1a38f2174250afe661c67a057eb8">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Agreement Technology</u></font>. As between the Parties, Biogen is and will be
                            the sole owner of any Know-How discovered, developed, invented or created solely by or on behalf of Biogen or its Affiliates under this Agreement (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                              font-style: italic;">Biogen Program Know-How</font>&#8221;) and any Patent Rights that claim or cover Biogen Program Know-How (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen











                              Program Patents</font>&#8221; and together with the Biogen Program Know-How, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Program Technology</font>&#8221;), and will
                            retain all of its rights, title and interests thereto, subject to any rights or licenses expressly granted by Biogen to Ionis under this Agreement. As between the Parties, Ionis is and will be the sole owner of any Know-How
                            discovered, developed, invented or created solely by or on behalf of Ionis or its Affiliates under&#160;this Agreement (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis
                              Program Know-How</font>&#8221;) and any Patent Rights that claim or cover such Know-How (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Program Patents</font>&#8221; and
                            together with the Ionis Program Know-How, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Program Technology</font>&#8221;), and will retain all of its rights, title and
                            interests thereto, subject to any assignment, rights or licenses expressly granted by Ionis to Biogen under this Agreement. Any Know-How discovered, developed, invented or created jointly under this Agreement by or on behalf of
                            both Parties or their respective Affiliates or Third Parties acting on their behalf (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Jointly-Owned Program Know-How</font>&#8221;)
                            and any Patent Rights that claim or cover such Jointly-Owned Program Know-How (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Jointly-Owned Program Patents</font>&#8221; and
                            together with the Jointly-Owned Program Know-How, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Jointly-Owned Program Technology</font>&#8221;), are and will be owned
                            jointly by Biogen and Ionis on an equal and undivided basis, including all rights, title and interests thereto, subject to any rights or licenses expressly granted by one Party to the other Party 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 Program
                            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. Each Party will promptly disclose to the other
                            Party in writing, and will cause its Affiliates to so disclose, the discovery, development, invention or creation of any Jointly-Owned Program Technology. The Biogen Program Patents, Ionis Program Patents and Jointly-Owned
                            Program Patents are collectively referred to herein as the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Program Patents</font>.&#8221;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">88</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z84cae0c6b9b54e52866c54e005d51cc3">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.1.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Joint Patent Committee</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z46c0e5e28f8d4b8c98345ebb297865a8">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Parties will establish a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Joint Patent Committee</font>&#8221;
                            or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">JPC</font>&#8221; promptly following the Effective Date.&#160; 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, with responsibilities including (i) the preparation of the intellectual property strategy to govern the Parties&#8217; activities set
                            forth in the Neurological Disease Research Plan and the activities set forth in this&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 7</u></font>, (ii) making recommendations following discussion by the
                            Parties regarding Third Party intellectual property rights that may be necessary or useful to perform activities under, and the intellectual property considerations to be taken into account in, the Neurological Disease Research
                            Plan, (iii) making recommendations with respect to intellectual property considerations to be taken into account in each ASO Development Candidate Identification Plan, (iv) the preparation of recommendations with respect to
                            intellectual property considerations in connection with proposed Development Candidates for consideration by the Parties, (v) assessing and making recommendations to the Neurology JDC prior to the completion of IND-Enabling
                            Toxicology Studies regarding any Patent Rights of any Third Party that may be necessary or useful for the Development, Manufacture or Commercialization of any Development Candidate that is the subject of such IND-Enabling
                            Toxicology Studies and (vi) evaluating any activities under a Neurology Plan that are proposed to be conducted with an academic or non-profit collaborator and making recommendations as to where and with whom such activities
                            should be conducted, and in each case will cooperate with respect to any such activities. Ionis&#8217; obligation to participate in the JPC will terminate on the later of (A) the end of the Research Term and (B) Biogen&#8217;s exercise of
                            (or the expiration or termination of) the last Option. Thereafter, Ionis will have the right, but not the obligation, to participate in JPC meetings, but shall nevertheless continue to coordinate with Biogen with respect to the
                            activities set forth in this&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 7</u></font>&#160;during the Agreement Term.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">89</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z995a69220f454917b944b4d103de7459">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The JPC will discuss a strategy and make recommendations with regard to intellectual property considerations (i) with respect to the Parties&#8217; activities under the
                            Core Research Program and the Neurological Disease Research Program, promptly following the Second Amendment Date&#160; and (ii) with respect to each Collaboration Program, promptly after such Collaboration Program is designated,
                            which strategies shall include (A) considerations for identifying potential inventions and making inventorship determinations, (B) considerations when selecting each Development Candidate, (C) considerations for Prosecution and
                            Maintenance, defense and enforcement of Ionis Product-Specific Patents that would be or are licensed to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font> in connection with
                            a Product, Biogen Product-Specific Patents and Jointly-Owned Program Patents, (D) defense against allegations of infringement of Third Party Patent Rights and (E) licenses to Third Party Patent Rights or Know-How, in each case
                            ((A) through (E)) to the extent such matter would be reasonably likely to have a material impact on the Agreement or the ownership of intellectual property or the licenses granted hereunder. The applicable strategy and the JPC&#8217;s
                            recommendations, as applicable, will be considered in good faith in the performance of the Neurology Plans, the preparation of the intellectual property assessment to be included in each Development Candidate Data Package<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">&#160;</font>and by the Party entitled to designate a Development Candidate or prosecute, enforce and defend such Patent Rights, as
                            applicable, hereunder, but will not be binding on such Party.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1b84005af9964f7eb1d17b7ba81b7b6f">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis or Biogen (as applicable) will provide the Joint Patent Committee with notice of any Know-How or Patent Rights discovered, developed, invented or created
                            jointly by such Party and a Third Party in the performance of activities under the Neurology Plans or solely by a Third Party performing activities under the Neurology Plans on such Party&#8217;s behalf (such Know-How and Patent
                            Rights, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaborator IP</font>&#8221;) promptly after such Party receives notice or otherwise becomes aware of the existence of
                            such Collaborator IP. The JPC will determine whether any such Collaborator IP would be infringed or misappropriated (as applicable) by the Development, Manufacture or Commercialization of the applicable Development Candidate or
                            any Compound under consideration by Ionis for potential designation as a Development Candidate. If the JPC (or independent patent counsel engaged pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                              </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.1.3(f))</u></font> determines that any Collaborator IP would be infringed or misappropriated (as applicable) by the Development, Manufacture or
                            Commercialization of such Development Candidate or Compound, [***]; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that</font>, if such Party is unable to obtain [***] license to
                            such Collaborator IP or if the Parties mutually agree that it is not necessary to obtain [***] license, then such Party shall use commercially reasonable efforts to obtain [***] license to such Collaborator IP from such Third
                            Party (any such [***] with such Third Party, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaborator License</font>&#8221;), and in each case, such Party will endeavor to
                            obtain in such Collaborator License the right to sublicense such Collaborator IP to the other Party on terms that contain no greater restrictions on the other Party&#8217;s use of such Collaborator IP than those set forth in this
                            Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">90</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8dfbeffeb20a46339ae48e5dda1a6bf7">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Notwithstanding any provision to the contrary in this Agreement, including under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.11</u></font>, if Collaborator IP (other than Additional Core IP arises from activities performed by a Third Party under the applicable Neurology Plan, then any
                            payment obligations arising under the applicable Collaborator License based on the Development or Commercialization of a Product will be [***] as follows: (i) in the case where [***] enters into such Collaborator License, [***]
                            will be solely responsible for paying any payment obligations that [***], except that [***] will be solely responsible for paying any payment obligations that [***] under any such Collaborator Licenses that [***] approved prior
                            to execution thereof, and (ii) in the case where [***] enters into such Collaborator License, [***] will be [***] responsible for paying any payment obligations that [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z85b59b73f6324f3a9168f5f4628b4021">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">With respect to any such Collaborator IP licensed by Ionis under a Collaborator License with such Third Party, Biogen will have the right in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.5</u></font> to elect to exclude any such Collaborator IP from the applicable license granted to Biogen under <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 4.1.1</u></font> by providing Ionis written notice prior to the License Effective Date&#160;for the applicable Collaboration Program. If, Biogen timely provides Ionis with such a written notice to
                            exclude certain of such Collaborator IP from such license, then such Collaborator IP will not be included in the Licensed Technology licensed with respect to such Collaboration Program under this Agreement. If Biogen does not
                            provide Ionis with such a written notice to exclude such Collaborator IP prior to the License Effective Date for the applicable Collaboration Program hereunder, then such Collaborator IP (and any Third Party Obligations to the
                            extent applicable to Products) will be included in the Licensed Technology licensed with respect to the applicable Collaboration Program under this Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">91</font></div>
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              <div>
                <div>
                  <div style="text-align: justify;">
                    <div>
                      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdb6ffa37cfb24171a88ab5d05cd22515">

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                            </td>
                            <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                            <td style="width: auto; vertical-align: top; text-align: justify;">
                              <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In case of a dispute in the Joint Patent Committee over whether any Collaborator IP would be infringed or misappropriated (as applicable) by the Development,
                                  Manufacture or Commercialization of the applicable Development Candidate or any Compound under consideration by Ionis for potential designation as the Development Candidate, at the non-contracting Party&#8217;s request, 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, taking into account any existing prior art. The
                                  decision of such independent patent counsel will be binding on the Parties. Expenses of such patent counsel will be borne by the non-contracting Party.</font></div>
                            </td>
                          </tr>

                      </table>
                      <div> <br>
                      </div>
                    </div>
                  </div>
                </div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd9439fcbdd7949f49ef0605d63dc6a4c">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(g)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In addition, the Joint Patent Committee will be responsible for the determination of inventorship of Patent Rights that claim or cover Know-How discovered,
                            developed, invented or created under this Agreement in accordance with United States patent Laws. In case of a dispute in the Joint Patent Committee (or otherwise between Ionis and Biogen) over inventorship of Program Patents,
                            if the Joint Patent Committee cannot resolve such dispute, even after seeking the CSC&#8217;s input, then 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.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2355f9a6fe654acca87a2bd2a08c5801">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(h)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 7</u></font>. The JPC will determine by unanimous consent of its members the JPC
                            operating procedures at its first meeting, including the JPC&#8217;s policies for replacement of JPC members, and the location of meetings, which will be codified in the written minutes of the first JPC 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 (up to the most senior intellectual property attorney, where appropriate)
                            with respect to critical issues, and may escalate issues to the Executives for input and resolution pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font>. 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.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9e1f4b0bc1644611ab4a4a80b6ed5323">

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                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Prosecution and Maintenance of Patents</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">92</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7f745980d1ae43e6a7b71edc497c7e2f">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.2.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patent Filings</u></font>. Subject to Biogen&#8217;s right to provide reasonable
                            input and comment as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.2.5(a)</u></font>, the Party responsible
                            for Prosecution and Maintenance of any Patent Rights as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.2</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                                7.2.3</u></font> will endeavor to obtain patent protection for the applicable 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z161690af81014f78a3c72978c7643e4b">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.2.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Licensed Patents and Biogen Patents</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3038f29bfab445108f51bb032abd9a54">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Licensed Patents In General</u></font>. Prior to the License Effective Date for
                            a Collaboration Program or Biogen Alternate Modality Program (as applicable) (a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Program</font>&#8221;), and subject to Biogen&#8217;s
                            right to provide reasonable input and comment as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.2.5(a)</u></font>,
                            Ionis will control and be responsible for all aspects of the Prosecution and Maintenance of all Licensed Patents that are the subject of such license grant for such Program, subject to this <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.2.2(a)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.3</u></font>.
                            During the Agreement Term, Ionis will control and be responsible for all aspects of the Ionis Core Technology Patents and Ionis Manufacturing and Analytical Patents. Ionis will use commercially reasonable efforts to diligently
                            Prosecute and Maintain all Jointly-Owned Program Patents for which Ionis has the right to Prosecute and Maintain. On a Program-by-Program, until the earlier of the License Effective Date with respect to such Program and the
                            expiration or termination of Biogen&#8217;s right to be granted such license, Ionis will use commercially reasonable efforts to diligently Prosecute and Maintain all Ionis Product-Specific Patents that are the subject of such Program
                            to the extent that Ionis has the right to Prosecute and Maintain such Patent Rights.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd9115614872242739b5912c7f225a528">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Licensed Patents After License </u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;"><u>Effective Date</u></font>. Upon the License Effective Date with respect to a Program, Biogen will control and be responsible for all aspects of the Prosecution and
                            Maintenance of all the Ionis Product-Specific Patents and Jointly-Owned Program Patents that are subject to the license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.1.1</u></font>&#160;for such Program to the same extent Ionis had the right to control and was responsible for such Prosecution and Maintenance immediately prior to
                            such License Effective Date, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.3</u></font>, and will grant Ionis the license set forth in <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 4.2.2</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za91e1e35a96f473887b04a32b3b0334b">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen Patents</u></font>. Biogen will control and be responsible for all
                            aspects of the Prosecution and Maintenance of all Biogen Patents, subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.3</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">93</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc54dbeae0452416da311ecf619966484">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.2.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Jointly-Owned Program Patents</u></font>. Subject to Biogen&#8217;s right to provide
                            reasonable input and comment as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.2.5(a)</u></font>, Ionis will
                            control and be responsible for all aspects of the Prosecution and Maintenance of Jointly-Owned Program Patents that do not Cover Products. Prior to the License Effective Date for a Program and subject to Biogen&#8217;s right to
                            provide reasonable input and comment as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.2.5(a)</u></font>,
                            Ionis will control and be responsible for all aspects of the Prosecution and Maintenance of Jointly-Owned Program Patents Covering Products that are the subject of such Program. After the License Effective Date for a
                            Collaboration Program, Biogen will control and be responsible for all aspects of the Prosecution and Maintenance of Jointly-Owned Program Patents Covering Products that are the subject of such Program.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za28548eee9d8410ebb309c253a66d401">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.2.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Prosecution of Multi-Indication Product-Specific Patents; Biogen Supremacy to
                                Enforce and Extend</u></font>.&#160; With respect to Product-Specific Patents related to Multi-Indication Products, the Parties will endeavor to prosecute such Patent Rights to claim inventions related to Neurological Diseases
                            separately from inventions related to Non-Neurological Indications. If there is an Ionis Product-Specific Patent that Covers both (a) a Multi-Indication Product licensed to Biogen under <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font>, and (b) a Multi-Indication Product of Ionis (each such Ionis Product-Specific Patent, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-weight: bold; font-style: italic;">Multi-Indication Product-Specific Patent</font>&#8221;), then so long as Biogen is Developing and Commercializing such Multi-Indication Product pursuant to its license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font>, upon the grant of such license, Biogen will have the sole and exclusive right, but not the obligation, to institute and control any (i)
                            Proceeding related to the infringement of such Multi-Indication Product-Specific Patent, (ii) Prosecution and Maintenance of such Multi-Indication Product-Specific Patent and (iii) patent term extension related to such
                            Multi-Indication Product-Specific Patent.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6d82b75f25f74363b75b937a82364997">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.2.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Other Matters Pertaining to Prosecution and Maintenance of Patents</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z42fd0d0907724b42be07d53bba907146">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will keep Biogen reasonably informed through the Joint Patent Committee (or directly, if the Joint Patent Committee has been disbanded) as to material
                            developments with respect to the Prosecution and Maintenance of (i) those Ionis Core Technology Patents and Ionis Manufacturing and Analytical Patents that Cover any Development Candidate or Product and (ii) the Ionis
                            Product-Specific Patents and Jointly-Owned Program Patents, in each case ((i) and (ii)), for which Ionis has the responsibility to Prosecute and Maintain pursuant to <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 7.2.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.3</u></font> or this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2.5</u></font>,
                            including by providing copies of material data as it arises. Ionis will timely provide Biogen the timely opportunity to have reasonable input into the strategic aspects of such Prosecution and Maintenance, including the
                            countries in which such Patent Rights are filed, and will consider Biogen&#8217;s input with respect to such strategic aspects in good faith but which will not be binding on Ionis. Additionally, Ionis will promptly provide to Biogen
                            drafts of all patent-related filings and communications related to the such Patent Rights, including copies of office actions or other correspondence that Ionis receives from any patent office, drafts of office action responses
                            or other correspondence that Ionis provides to any patent office, and copies and drafts of all interferences, reissues, re-examinations, oppositions or requests for patent term extensions, in each case, for Biogen&#8217;s review and
                            comment, and Ionis will consider in good faith any reasonable comments timely provided by Biogen with respect to such draft filings and communications.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">94</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z04276925358f41899a4c053979d6dfeb">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Following the License Effective Date with respect to a particular Program, Biogen will keep Ionis reasonably informed through the Joint Patent Committee (or
                            directly, if the Joint Patent Committee has been disbanded) as to material developments with respect to the Prosecution and Maintenance of Product-Specific Patents or Jointly-Owned Program Patents for which Biogen has the
                            responsibility to Prosecute and Maintain pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.2.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.2.3</u></font>&#160;or this <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.2.5</u></font>, including by providing copies of material data as it arises and will provide Ionis the timely opportunity to
                            have reasonable input into the strategic aspects of such Prosecution and Maintenance, which input Biogen will consider in good faith but which will not be required to implement. Following the License Effective Date with respect
                            to a particular Program, Biogen will have final decision-making authority with respect to the Prosecution and Maintenance, enforcement and defense of such Product-Specific Patents or Jointly-Owned Program Patents related to such
                            Program, including any Proceeding related to the infringement of such Patent Rights and any patent term extensions related to such Patent Rights.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z65cc654ab364447b8151ff70e8a83e54">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Biogen elects (i) not to file and prosecute patent applications for the Jointly-Owned Program Patents or Ionis Product-Specific Patents that have been licensed
                            or assigned to Biogen under this Agreement or the Biogen Product-Specific Patents (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen-Prosecuted Patents</font>&#8221;) in a
                            particular country, (ii) not to continue the Prosecution and Maintenance (including any interferences, oppositions, reissue proceedings, re-examinations, and patent term extensions, adjustments, and restorations) of any
                            Biogen-Prosecuted Patent in a particular country or (iii) not to file and prosecute patent applications for the Biogen-Prosecuted Patent in a particular country following a written request from Ionis to file and prosecute in
                            such country, then in each case ((i) &#8211; (iii)), Biogen will so notify Ionis promptly in writing of its intention (including a reasonably detailed rationale for doing so) with sufficient time to enable Ionis to meet any deadlines
                            by which an action must be taken to establish or preserve any such Patent Right in such country; and except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.2.5(d)</u></font> Ionis will have the right, but not the obligation, to file, prosecute, maintain, enforce or otherwise pursue such Biogen-Prosecuted Patent in the
                            applicable country at its own expense with counsel of its own choice. In such case, Biogen will cooperate with Ionis to file for, or continue to Prosecute and Maintain, enforce or otherwise pursue such Biogen-Prosecuted Patent
                            in such country in Ionis&#8217; own name, but only to the extent that Biogen is not required to take any position with respect to such abandoned Biogen-Prosecuted Patent that would be reasonably likely to adversely affect the scope,
                            validity or enforceability of any of the other Patent Rights being prosecuted and maintained by Biogen under this Agreement. Notwithstanding anything to the contrary in this Agreement, if Ionis assumes responsibility for the
                            Prosecution and Maintenance of any such Biogen-Prosecuted Patent under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.2.5(c)</u></font>,
                            then Ionis will have no obligation to notify Biogen if Ionis intends to abandon such Biogen-Prosecuted Patent.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">95</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb1006b8f405e4e65b4ba547ea2e97009">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Notwithstanding <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>7.2.5(c)</u></font> above, if, after having consulted with outside counsel, Biogen reasonably determines that filing or continuing to prosecute a patent application in a particular country for a Biogen-Prosecuted
                            Patent (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Conflicting Patent Right</font>&#8221;) is reasonably likely to adversely affect the scope, validity or enforceability
                            of a patent application or issued patent in a particular country for another Biogen-Prosecuted Patent (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Superior Patent
                              Right</font>&#8221;), in each case where both the Conflicting Patent Right and the Superior Patent Right if issued would meet the criteria set forth in clause (i) of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                                6.10.2(a)</u></font>, then <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">so long as</font> Biogen continues to Prosecute and Maintain the Superior Patent Right in accordance with this
                            Agreement, Ionis will not have the right under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.2.5(c)</u></font> above to
                            file or prosecute the Conflicting Patent Right.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z10f7f08d566349fda40309ded0533428">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, during the Agreement Term, Ionis intends not to file or to abandon in any jurisdiction any Ionis Product-Specific Patent for which Ionis is responsible for
                            Prosecution and Maintenance without first filing a continuation or substitution, then, if Biogen&#8217;s right to obtain a license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1</u></font> to
                            such Ionis Product-Specific Patent has not expired or terminated, Ionis will notify Biogen of such intention at least [***] days before such Patent Right will become abandoned, and Biogen will have the right, but not the
                            obligation, to assume responsibility and final decision-making authority for the Prosecution and Maintenance thereof at its own expense (subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.3.1</u></font>)
                            with counsel of its own choice.&#160; Notwithstanding anything to the contrary in this Agreement, if Biogen assumes responsibility for the Prosecution and Maintenance of any such Ionis Product-Specific Patent under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.2.5(e)</u></font>, then Biogen will have no obligation to notify Ionis if
                            Biogen intends to abandon such Ionis Product-Specific Patent.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">96</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z66517f8c291f4363b70f76f7a01fc74a">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Parties, through the Joint Patent Committee (or directly, if the Joint Patent Committee has been disbanded), will cooperate in good faith to determine if and
                            when any divisional or continuation applications will be filed with respect to any Program Patents or Product-Specific Patents, and where a divisional or continuation patent application filing would be practical and reasonable,
                            following which determination such a divisional or continuation filing will be made.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfbf960cc3b684cc19f51e0e35ca2e4d6">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(g)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If the Party responsible for Prosecution and Maintenance of a Jointly-Owned Program Patent pursuant to <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 7.2.3</u></font> intends to abandon such Jointly-Owned Program Patent without first filing a continuation or substitution, then such Party will notify the other Party of such intention at least [***] days
                            before such Jointly-Owned Program Patent will become abandoned, and such other Party will have the right, but not the obligation, to assume responsibility and final decision-making authority for the Prosecution and Maintenance
                            thereof at its own expense (subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.3.1</u></font>) 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 interests in and to such Jointly-Owned Program Patents. If a Party assumes
                            responsibility for the Prosecution and Maintenance of any such Jointly-Owned Program Patents under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>7.2.5(g)</u></font>, such Party will have no obligation to notify the other Party of any intention of such Party to abandon such Jointly-Owned Program Patents.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbc9cbc125ec54ee0a9a1ceb35f78b85d">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(h)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In addition, the Parties will consult, through the Joint Patent Committee (or directly, if the Joint Patent Committee has been disbanded), 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.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfb8322a324f54f1fa6de95f38ab916cc">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patent Costs</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfc4d58600bd14de2b30458ca44919a57">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.3.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Jointly-Owned Program Patents</u></font>. Unless the Parties agree otherwise,
                            Ionis and Biogen will share equally the Patent Costs associated with the Prosecution and Maintenance of Jointly-Owned Program Patents; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided
                            </font>that either Party may decline to pay its share of costs for filing, prosecuting and maintaining any Jointly-Owned Program 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 Program
                            Patents.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">97</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2d490bdc5d834a22b04dbe78d6467aee">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.3.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Licensed Patents and Biogen Patents</u></font>. Except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.3.1</u></font>, 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.2</u></font>; <font style="font-size: 10pt; font-family: 'Times
                              New Roman'; font-style: italic;">provided, however</font>, that after the License Effective Date for a Program, Biogen will be solely responsible for Patent Costs arising from the Prosecution and Maintenance of the Ionis
                            Product-Specific Patents related to such Program.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0341fc337a284cd6a03db32881f70925">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Defense of Claims Brought by Third </u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;"><u>Parties</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z21be9c65ea91426296f463a17f799a27">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.4.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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) Ionis will have the first right, but not the obligation, to defend against any such Proceeding initiated prior to the License Effective Date for the applicable Program at its sole cost and
                            expense, and (b) Biogen will have the first right, but not the obligation, to defend against any such Proceeding initiated after the License Effective Date for the applicable Program at its sole cost and expense. If the Party
                            having the first right to defend against such Proceeding (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.4</u></font>, and the Lead Party will keep the other
                            Party apprised of the progress of such Proceeding. Notwithstanding the foregoing, (i) if Ionis is the Lead Party, then Ionis will cooperate in good faith with Biogen on the institution, prosecution and control of such
                            Proceeding, will provide Biogen with copies of filings, submissions and communications related to such Proceeding in sufficient time to allow Biogen to review and comment thereon, and will incorporate any reasonable comments
                            timely provided by Biogen with respect to such filings, submissions and communications and (ii) if Biogen is the Lead Party and Ionis is a named party, then Biogen will cooperate in good faith with Ionis on the institution,
                            prosecution and control of such Proceeding and will provide Ionis the timely opportunity to have reasonable input into the strategic aspects of such Proceeding, which Biogen will consider in good faith but which will not be
                            required to implement. If the Lead Party elects not to defend against a Proceeding, then the Lead Party will so notify the other Party in writing within [***] days after the Lead Party first receives written notice of the
                            initiation of such Proceeding, and the other Party (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.4</u></font>. Each Party will provide the other Party with prompt written notice
                            of the commencement of any such Proceeding under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.4</u></font>, 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.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">98</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbef8fff176874f259900ad5a9a5ce09e">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.4.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Discontinued Collaboration Product</u></font>. 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 Collaboration Product, then Ionis will have the
                            first right, but not the obligation, to defend against and settle such Proceeding at its sole cost and expense. Biogen will reasonably assist Ionis in defending such Proceeding and cooperate in any such litigation at the request
                            and expense of Ionis. Each Party may at its own expense and with its own counsel join any defense directed by the other Party. Ionis will provide Biogen with prompt written notice of the commencement of any such Proceeding, or
                            of any allegation of infringement of which Ionis becomes aware and that is of the type described in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.4.2</u></font>, and Ionis will promptly
                            furnish Biogen with a copy of each communication relating to the alleged infringement received by Ionis.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze4496ae6108b488dba0a334290b804f5">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.4.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Interplay Between Enforcement of IP and Defense of Third Party Claims</u></font>.&#160;&#160;












                            Notwithstanding the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.4.1</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.4.2</u></font>, to
                            the extent that a Party&#8217;s defense against a Third Party claim of infringement under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.4</u></font> involves (a) the enforcement of the other Party&#8217;s
                            Know-How or Patent Rights (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>, a counterclaim of infringement), or (b) 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.5</u></font> will apply to the enforcement of such other Party&#8217;s Know-How or Patent
                            Rights or the defense of such invalidity claim (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font>, 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.5</u></font>, 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.5</u></font>, to enforce such Know-How or Patent Rights or
                            defend such invalidity claim).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">99</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z51282c53a4b546669ec4d8e1b5785a48">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Enforcement of Patents Against Competitive Infringement</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zeb0d52e5160042bd86f0e4fef499d705">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.5.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Duty to Notify of Competitive Infringement</u></font>. 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 conflicting obligation of confidentiality with respect to any Licensed Patents by reason of
                            the development, manufacture, use or commercialization of (i) a product directed against the RNA that encodes a Collaboration Target in the Field, or (ii) a non-Oligonucleotide product that is designed to bind, mimic or
                            otherwise affect a protein or RNA that is encoded by a Biogen Alternate Modality Target (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competitive</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided,
                              however</font>, that for cases of Competitive Infringement under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.5.8</u></font>
                            below, such written notice will be given within 10 days.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z51853fa553184258809b458585b10f35">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.5.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Prior to License Grant</u></font>.<font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-weight: bold;">&#160;</font>For any Competitive Infringement with respect to a Product occurring after the Effective Date but before the License Effective Date for the Program of which such Product is the
                            subject, Ionis 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 Biogen will have the right to be represented in that
                            action by counsel of its own choice at its own expense. Ionis will provide Biogen with prompt written notice of the commencement of any such Proceeding, and Ionis will keep Biogen apprised of the progress of such Proceeding.
                            Additionally, Ionis will provide Biogen with copies of filings, submissions and communications related to such Proceeding in sufficient time to allow Biogen to review and comment thereon, and will consider in good faith any
                            reasonable comments timely provided by Biogen with respect to such filings, submissions and communications. Subject to the preceding sentence, Ionis will have the sole right to control such litigation. If Ionis fails to initiate
                            a Proceeding within a period of 90 days after receipt of written notice of such Competitive Infringement (subject to a 90 day extension to conclude negotiations, which extension will apply only in the event that Ionis has
                            commenced good faith negotiations with an alleged infringer for elimination of such Competitive Infringement within such 90 day period), Biogen 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided </font>that Ionis will have the right to be represented in any such action by
                            counsel of its own choice at its own expense. Notwithstanding the foregoing, Ionis will at all times have the sole right to institute, prosecute, and control any Proceeding under this <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 7.5.2</u></font> to the extent involving any Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbb4f0d115f1d4fc0b4dc49d6fc41004a">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.5.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen Enforcement Rights</u></font>. Notwithstanding <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.5.2</u></font>&#160;and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.5.4</u></font>, in the case where a Third Party is infringing an Ionis Core Technology Patent and a Patent Right Controlled by Biogen by reason of the development,
                            manufacture, use or commercialization of a product directed against the RNA that encodes a High Interest Target, Collaboration Target in the Field, then such Party will promptly notify the other Party in writing. If Biogen also
                            enforces any Patent Rights Controlled by Biogen (including any Ionis Product-Specific Patents assigned by Ionis to Biogen under this Agreement) against such infringement, then Biogen may elect to have Ionis and Biogen enforce
                            the applicable Ionis Core Technology Patents and the applicable Patent Rights Controlled by Biogen against such infringing Third Party.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">100</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1726c2eab24a4b938a5ab0e775118bb9">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.5.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Following License Grant</u></font>. For any Competitive Infringement with
                            respect to a particular Product (except for a Discontinued Collaboration Product) occurring after the License Effective Date for the Program of which such Product is the subject, so long as part of such Proceeding Biogen also
                            enforces any Patent Rights Controlled by Biogen (including any Ionis Product-Specific Patents assigned by Ionis to Biogen under this Agreement) being infringed that Cover the Product, then Biogen 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 Ionis will have the right, at its own expense, to be represented in that action by
                            counsel of its own choice, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">however,</font> Biogen will have the right to control such litigation. If Biogen fails to initiate a Proceeding
                            within a period of 90 days after receipt of written notice of such Competitive Infringement (subject to a 90 day extension to conclude negotiations, if Biogen has commenced good faith negotiations with an alleged infringer for
                            elimination of such Competitive Infringement within such 90 day period), Ionis will have the right to initiate and control a Proceeding with respect to such Competitive Infringement by counsel of its own choice, and Biogen will
                            have the right to be represented in any such action by counsel of its own choice at its own expense. Notwithstanding the foregoing, Ionis will at all times have the sole right to institute, prosecute, and control any Proceeding
                            under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.5.4</u></font> to the extent involving any Ionis Core
                            Technology Patents or Ionis Manufacturing and Analytical Patents.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z783fb02017b3453ea63852b8eeebe414">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.5.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Joinder</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbd5ff07d42e74c41bc4063e1c6961e25">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If a Party initiates a Proceeding in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.5</u></font>, then the other
                            Party agrees to be joined as a party plaintiff where necessary and to give the first Party reasonable assistance and authority to file and prosecute the Proceeding. Subject to <font style="font-size: 10pt; font-family: 'Times
                              New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.5.6</u></font>, the costs and expenses of each Party incurred pursuant to this <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.5.5(a)</u></font> will be borne by the Party initiating such Proceeding.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z82ae69828e904914a6c6b0f36044e11f">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If one Party initiates a Proceeding in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.5.5</u></font>, then the other Party may join such Proceeding as a party plaintiff where necessary for such other Party to seek lost profits with respect to such
                            infringement or where such Proceeding relates to Jointly-Owned Program Patents.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">101</font></div>
              <div id="DSPFPageBreak" style="page-break-after: always;">
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za6132820aeae4f9dbf21f84c8f20f153">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.5.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Share of Recoveries</u></font>. Any damages or other monetary awards recovered
                            with respect to a Proceeding brought pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.5</u></font> will be shared as follows:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8fb35dfdff5f4a608091cc2bbd415402">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">pro rata</font> if insufficient to cover the totality of such expenses); then</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6d409bf9a38e42d79b90a059fcd0ba27">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any remaining proceeds constituting direct or actual damages for acts of infringement occurring prior to the License Effective Date for the Program of which the
                            applicable Product is the subject will be (i) [***]; or (ii) [***]; then</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2ac0390938eb44c5af69379403627663">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any remaining proceeds constituting direct or actual damages for acts of infringement occurring after the License Effective Date for the Program of which the
                            applicable Product is the subject [***]; then</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfd782b8b0ec541fd9c415af8689e69e4">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 [***]% of such proceeds and the other Party will receive and retain [***]% of such proceeds.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd54fec9347f540149d8c8dca50c4aada">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.5.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Settlement</u></font>. Notwithstanding anything to the contrary under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 7</u></font>, neither Party may enter a settlement, consent judgment or other voluntary final disposition of a suit under this <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>ARTICLE 7</u></font> 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd34e26f52e1040a7bddee1ea20212126">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.5.8.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>35 USC 271(e)(2) Infringement</u></font>. Notwithstanding anything to the
                            contrary in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.5</u></font>, solely with respect to Licensed Patents that have not been assigned to Biogen under this Agreement for a Competitive
                            Infringement under 35 USC 271(e)(2), the time period set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.5.2</u></font> during which a Party will have the initial right to bring a Proceeding
                            will be shortened to a total of 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 25 days after such first Party&#8217;s receipt of written notice of such Competitive Infringement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">102</font></div>
              <div id="DSPFPageBreak" style="page-break-after: always;">
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf54ac8797dba4d06acb681e5a6777453">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Other Infringement</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc796f31ffdcd4ecaab481e65cde7e3ed">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.6.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Jointly-Owned Program Patents</u></font>. With respect to the infringement of a
                            Jointly-Owned Program 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.6.1</u></font> will be shared as follows:
                            (a) 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-size: 10pt; font-family: 'Times
                              New Roman'; font-style: italic;">pro rata</font> if insufficient to cover the totality of such expenses); (b) any remaining proceeds constituting direct damages will be [***], and (c) any remaining proceeds constituting
                            punitive or treble damages will be allocated as follows: (i) if the Parties jointly initiate a Proceeding pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.6.1</u></font>, [***]; and
                            (ii) if only one Party initiates the Proceeding pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.6.1</u></font>, such Party will receive [***]% of such proceeds and the other Party
                            will receive [***]% of such proceeds.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5afade550d0b47f2817eea5a22de8d69">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.6.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patents Solely Owned by Ionis</u></font>. Ionis will retain all rights to
                            pursue an infringement of any Patent Right solely owned by Ionis which is other than a Competitive Infringement and Ionis will retain all recoveries with respect thereto.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zcc61474da7df4179a244a10aae9794b5">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.6.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patents Solely Owned by Biogen</u></font>. Biogen will retain all rights to
                            pursue an infringement of any Patent Right solely owned by Biogen which is other than a Competitive Infringement and Biogen will retain all recoveries with respect thereto.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8a88a07d6ee24837adfc2d0b660d3fff">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patent Listing</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z49b8419b91394847b6a93217669b27ef">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.7.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen&#8217;s Obligations</u></font>. Biogen 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 Biogen 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, Biogen will retain final decision-making authority as to the listing of all applicable Patent Rights for the Product that are not Ionis Core Technology
                            Patents or Ionis Manufacturing and Analytical Patents, regardless of which Party owns such Patent Rights.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">103</font></div>
              <div id="DSPFPageBreak" style="page-break-after: always;">
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc8d9c19faf81456d9722dc859bf70dff">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.7.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Obligations</u></font>. Ionis will promptly, accurately and completely
                            list, with the applicable Regulatory Authorities during the Agreement Term, all applicable Patent Rights that Cover a Discontinued Collaboration Product. Prior to such listings, the Parties will meet, through the Joint Patent
                            Committee, to evaluate and identify all applicable Patent Rights, and Ionis 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, Ionis will retain final decision-making authority as to the listing of all applicable Patent Rights for such Discontinued Collaboration Products, as
                            applicable, regardless of which Party owns such Patent Rights.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0c31cf79ca6b4c939cf84956ec5b8948">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.8.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Joint Research Agreement under the Leahy-Smith America Invents Act</u></font>.
                            Notwithstanding anything to the contrary in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 7</u></font>, neither Party will have the right to make an election under 35 U.S.C. &#167; 102(c) of the
                            Leahy-Smith America Invents Act when exercising its rights under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 7</u></font> without the prior written consent of the other Party, which will not
                            be unreasonably withheld, conditioned or delayed.&#160; With respect to any such permitted election, each Party will use reasonable efforts to cooperate and coordinate their activities with the other Party with respect to any
                            submissions, filings or other activities in support thereof. The Parties acknowledge and agree that this Agreement is a &#8220;joint research agreement&#8221; as defined in 35 U.S.C. &#167; 100(h).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zab282fae50e04fbd8f145d5c585f1fda">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.9.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Obligations to Third Parties</u></font>. Notwithstanding any of the foregoing,
                            each Party&#8217;s rights and obligations with respect to Licensed Technology under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 7</u></font> will be subject to the Third Party rights and obligations
                            under any (a) New Third Party License the restrictions and obligations of which Biogen has agreed to under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.2</u></font>, (b) Prior Agreements, and
                            (c) Ionis In-License Agreements; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that, to the extent that Ionis has a non-transferable right to prosecute, maintain or
                            enforce any Patent Rights licensed to Biogen hereunder and, this Agreement purports to grant any such rights to Biogen, Ionis will act in such regard with respect to such Patent Rights at Biogen&#8217;s direction.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6e7b6ee399994672a6b524527972fa46">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">7.10.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Additional Right and Exceptions</u></font>. Notwithstanding any provision of
                            this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 7</u></font>, Ionis retains the sole right to Prosecute and Maintain Ionis Core Technology Patents and Ionis Manufacturing and Analytical Patents
                            during the Agreement Term and to control any enforcement of Ionis Core Technology Patents and Ionis 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 Ionis and Covering the Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents is at risk.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div id="DSPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">104</font></div>
              <div id="DSPFPageBreak" style="page-break-after: always;">
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            </div>
          </div>
          <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z837fde16f903404db67875d9780ec1c4">

              <tr>
                <td style="width: 36pt; vertical-align: top; align: right; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">7.11.</td>
                <td style="width: auto; vertical-align: top; text-align: justify;">
                  <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Patent Term Extension</u></font>. The Parties will cooperate with each other in
                      gaining patent term extension wherever applicable to the Product. After the License Effective Date for the Collaboration Program of which such Product is the subject, Biogen will have the sole right to determine which relevant patents
                      will be extended.</font></div>
                </td>
              </tr>

          </table>
        </div>
        <div>
          <div>
            <div style="text-align: justify;"> </div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 8.</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">REPRESENTATIONS AND WARRANTIES</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8e352394cc8a4c83b35b0fa0f48acba5">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Representations and Warranties of Both Parties</u></font>. Each Party hereby
                            represents and warrants to the other Party, as of the Second Amendment Date, that:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf79d0e78bae343dd9e275d78b486fc84">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5f09f327ea7f4b71b36406b5ab828726">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z550755a83fbe4413b442b9a8f85229a8">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z58b90d08061a4dd6902734feb5a739a4">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 violate any law or regulation of any court, governmental body or administrative or other agency having jurisdiction over such Party;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z27d814a939c44867b8afedde7760b410">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">105</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9dd17e3c83b24e9892606e52ac2105a6">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.1.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">it has not employed (and, to the best of its knowledge, 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, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> 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 the Product and its activities under each Collaboration Program.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbc762c9ee53b48b49bf4e9b347072efe">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Representations and Warranties of Ionis</u></font>. Ionis hereby represents and
                            warrants to Biogen, as of the Effective Date, that:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9651c9597f794775b8bd1413a781a40f">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">To the best of its knowledge and belief, there are no additional licenses (beyond those that would be granted to Biogen under <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> upon the exercise of the Option for a Collaboration Product arising under the Collaboration Programs) under any intellectual property owned or Controlled by Ionis
                            or its Affiliates as of the Effective Date that would be required in order for Biogen to further Develop and Commercialize a Collaboration Product.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6a58de5584594dd9b7758b79819b7fe7">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Licensed Technology existing as of the Effective Date constitutes all of the Patent Rights and Know-How Controlled by Ionis as of the Effective Date that are
                            necessary to Develop, Manufacture or Commercialize Compounds contemplated under the Collaboration Programs in the Field. Ionis 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 Biogen hereunder with respect to Collaboration Products.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z858ed0674c714c7883ce2caa3ac876e5">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Neither Ionis nor its Affiliates owns or Controls any Patent Rights or Know-How covering formulation or delivery technology as of the Effective Date that would be
                            useful or necessary in order for Biogen to further Develop or Commercialize Compounds contemplated under the Collaboration Programs.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zee65fb6ffe58477f9f90adc5cdd78698">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u> 8.2.4(a)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 8.2.4(b)</u></font>
                            set forth true, correct and complete lists of all Ionis Core Technology Patents and Ionis Manufacturing and Analytical Patents that apply to the Compounds contemplated under the Collaboration Programs as of the Effective Date
                            (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Platform Technology</font>&#8221;), respectively, and indicates whether each such Patent Right is owned by Ionis or
                            licensed by Ionis from a Third Party and if so, identifies the licensor or sublicensor from which the Patent Right is licensed.&#160; Ionis 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 Biogen under this Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">106</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9447b5e0a30d4345b657d10deeaf0e37">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">There are no claims, judgments or settlements against or owed by Ionis or its Affiliates or pending against Ionis or, to the best of Ionis&#8217; knowledge, threatened
                            against Ionis, in each case relating to the Ionis Platform Technology, Ionis Manufacturing and Analytical Know-How, Ionis Know-How, Collaboration Targets or High Interest Targets that could impact activities under this
                            Agreement. To the best of Ionis&#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 Ionis Platform Technology, Ionis Manufacturing and Analytical Know-How, Ionis Know-How or High Interest Targets that would impact activities under this
                            Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za583cf82472a43398f87170f265c6ff0">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">At the Effective Date (a) there is no fact or circumstance known by Ionis that would cause Ionis to reasonably conclude that any Ionis Core Technology Patent or
                            Ionis Manufacturing and Analytical Patent is invalid or un-enforceable, (b) there is no fact or circumstance known by Ionis that would cause Ionis to reasonably conclude the inventorship of each Ionis Core Technology Patent or
                            Ionis Manufacturing and Analytical Patent is not properly identified on each patent, and (c) all official fees, maintenance fees and annuities for the Ionis Core Technology Patent or Ionis Manufacturing and Analytical Patent
                            have been paid and all administrative procedures with governmental agencies have been completed.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3164c4594c6b432a938fa376d8213650">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis has set forth on<font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;">&#160;</font><font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 6.13.1</u></font> or in a separate written agreement with Biogen true, correct and complete
                            lists of the agreements with Third Party licensors or sellers pursuant to which Ionis has licensed or acquired the Licensed Technology Controlled by Ionis as of the Effective Date licensed to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> that is necessary or useful to conduct the research, Development, Manufacture or Commercialization of any High Interest Target listed on
                            the High Interest Target List as of the Effective Date.&#160; All Ionis In-License Agreements are in full force and effect and have not been modified or amended. Neither Ionis nor, to the best knowledge of Ionis, the Third Party
                            licensor in an Ionis In-License Agreement is in default with respect to a material obligation under such Ionis 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 Ionis In-License Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd2fc7fb566554003accc4a355aaa2dbc">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.2.8.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u> 8.2.8</u></font> is a complete and accurate list of all agreements that create Third Party Obligations with respect to the Ionis Core Technology Patents and Ionis Manufacturing and Analytical Patents that affect
                            the rights granted by Ionis to Biogen under this Agreement with respect to Collaboration Programs.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">107</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd5374a3960fb44b6a43c5eb895957453">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis Covenants</u></font>. Ionis hereby covenants to Biogen that, except as
                            expressly permitted under this Agreement:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z35bd2b5bfbd443328a802e21355f5011">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.3.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will promptly amend <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u> 8.2.4(a)</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times
                              New Roman';"><u> 8.2.4(b)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>
                                8.2.4(c)</u></font> and submit such amended Schedules to Biogen if Ionis becomes aware that any Ionis Core Technology Patents, Ionis Manufacturing and Analytical Patents or Ionis Product-Specific Patents are not properly
                            identified on such Schedule.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdcc750aaaa024feaa213b8541d2e684f">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.3.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">during the Agreement Term, Ionis will maintain and not breach any Ionis In-License Agreements and any agreements with Third Parties entered into after the Effective
                            Date (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">New Third Party Licenses</font>&#8221;) that provide a grant of rights from such Third Party to Ionis that are Controlled by
                            Ionis and are licensed or may become subject to a license from Ionis to Biogen for a Development Candidate under this Agreement;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6f5d25f686374aa08ef8a9d7973f8e57">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.3.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will promptly notify Biogen of any material breach by Ionis or a Third Party of any New Third Party License, and in the event of a breach by Ionis, will
                            permit Biogen to cure such breach on Ionis&#8217; behalf upon Biogen&#8217;s request;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd7d5c2f8b03c4e918664445f40a90fc3">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.3.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will not amend, modify or terminate any Ionis In-License Agreement or New Third Party License in a manner that would adversely affect Biogen&#8217;s rights
                            hereunder without first obtaining Biogen&#8217;s written consent, which consent may be withheld in Biogen&#8217;s sole discretion;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z62153ed7578840b9acd506d47fe7ee6a">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.3.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis 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 Biogen under this Agreement;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5cb1496525714ae682a74079f1f8673c">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.3.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will cause its Affiliates, to comply with the terms of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1</u></font> and will not
                            permit any Affiliates to conduct any activities that Ionis is prohibited from conducting under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>2.1</u></font>;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zeb1fe9cb6f264ac2a6940a1261f986fa">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.3.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">all employees and contractors of Ionis performing Development activities hereunder on behalf of Ionis will be obligated to assign all right, title and interest in
                            and to any inventions developed by them, whether or not patentable, to Ionis or such Affiliate, respectively, as the sole owner thereof; and</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd26445ea30af4bcf9232e4fb01cbee49">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.3.8.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, after the Effective Date, Ionis becomes the owner or otherwise acquires Control of any formulation or delivery technology that would be necessary or useful in
                            order for Biogen to further Develop, Manufacture or Commercialize a Collaboration Product, and Biogen has exercised its Option and the license granted to Biogen under this Agreement is in effect, Ionis will make such technology
                            available to Biogen on commercially reasonable terms.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">108</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5270bfaefc424c749888af6d92e3d5a6">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">8.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>DISCLAIMER</u></font>. 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. BIOGEN AND IONIS
                            UNDERSTAND THAT EACH PRODUCT IS THE SUBJECT OF ONGOING RESEARCH AND DEVELOPMENT AND THAT NEITHER PARTY CAN ASSURE THE SAFETY, USEFULNESS OR COMMERCIAL OR TECHNICAL VIABILITY OF EACH PRODUCT<font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;">.</font></font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 9.</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">INDEMNIFICATION; INSURANCE</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z27abf401fda84bd280fdd4ec6970ebac">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Indemnification by Biogen</u></font>. Biogen will indemnify, defend and hold
                            harmless Ionis 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-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Claims</font>&#8221;) based upon:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za09ce4d981a3478e94297019aee8088b">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.1.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the gross negligence or willful misconduct of Biogen, its Affiliates or Sublicensees and its or their respective directors, officers, employees and agents, in
                            connection with Biogen&#8217;s performance of its obligations or exercise of its rights under this Agreement;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2fc775f6480049b880f5b8f5bf719c53">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.1.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any breach of any representation or warranty or express covenant made by Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 8</u></font>
                            or any other provision under this Agreement;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z415408a549ba406c978b8bb76aa0aaf2">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.1.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the Development or Manufacturing activities that are conducted by or on behalf of Biogen or its Affiliates or Sublicensees (which will exclude any Development or
                            Manufacturing activities that are conducted by or on behalf of Ionis pursuant to this Agreement); or</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8e2760bb7e454b84a3feff8ad7369a54">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.1.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the Commercialization of a Product by or on behalf of Biogen or its Affiliates or Sublicensees;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">except, in each case above, to the extent such Claim arose out of or resulted from or is attributable to any acts or omissions
                of Ionis or its Affiliates, licensees, Sublicensees or contractors, and it&#8217;s or their respective directors, officers, employees and agents or other circumstance for which Ionis has an indemnity obligation pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">109</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0af2619ba5ac4d24a6c086f23e55fc67">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Indemnification by Ionis</u></font>. Ionis will indemnify, defend and hold
                            harmless Biogen 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2010654f424d48698a3cd6e0cf0eaabc">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.2.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the gross negligence or willful misconduct of Ionis, its Affiliates or Sublicensees or its or their respective directors, officers, employees and agents, in
                            connection with Ionis&#8217; performance of its obligations or exercise of its rights under this Agreement;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z84f5ac4b19194c64b805477ce8de3856">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.2.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any breach of any representation or warranty or express covenant made by Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 8</u></font>
                            or any other provision under this Agreement;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb0dadc3548244edcb9c4fd1a044af844">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.2.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any Development or Manufacturing activities that are conducted by or on behalf of Ionis or its Affiliates or Sublicensees (which will exclude any Development or
                            Manufacturing activities that are conducted by or on behalf of Biogen pursuant to this Agreement); or</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd30d16cffb1e486892e159ab9e4460fc">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.2.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">any development, manufacturing or commercialization activities that are conducted by or on behalf of Ionis or its Affiliates or Sublicensees with respect to a
                            Discontinued Collaboration Product.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">except, in each case above, to the extent such Claim arose out of or resulted from or is attributable to any acts or omissions
                of Biogen or its Affiliates, licensees, Sublicensees or contractors and its or their respective directors, officers, employees and agents or other circumstance for which Biogen has an indemnity obligation pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zead5986bf9e149eca4fa5827e2826e88">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Procedure</u></font>. If a Person entitled to indemnification under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.1</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.2</u></font> (an &#8220;<font style="font-size: 10pt; font-family:
                              'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that (A) 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 and (B) the indemnifying Party first obtain the written consent of the Indemnitee with respect to such settlement, which
                            consent will not be unreasonably withheld), (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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.4</u></font> 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.1</u></font> or <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 9.2</u></font>, 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>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">110</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0db623889cac43ccbd86eb6825d5be8c">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Insurance</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbf7f589e6fd244938e4b1004d63d492c">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.4.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Insurance Obligations</u></font>. Ionis will maintain, at its cost,
                            reasonable insurance against liability and other risks associated with its activities contemplated by this Agreement, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, that</font>, at
                            a minimum, Ionis will maintain, in force from [***] days prior to enrollment of the first patient in a Clinical Study, a [***] insurance policy providing coverage of at least $[***] per claim and $[***] Annual aggregate. Ionis
                            will furnish to Biogen evidence of such insurance upon request.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z49ed90136b5d46649c33a203980be728">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.4.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen&#8217;s Insurance Obligations</u></font>. Biogen will maintain, at its cost,
                            reasonable insurance against liability and other risks associated with its activities contemplated by this Agreement, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, that</font>, at
                            a minimum, Biogen will maintain, in force from [***] days prior to enrollment of the first patient in a Clinical Study, a [***] insurance policy providing coverage of at least $[***] per claim and $[***] Annual aggregate and, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided further</font> that such coverage is increased to at least $[***] at least [***] days before Biogen initiates the First Commercial Sale of a
                            Product hereunder. Biogen will furnish to Ionis evidence of such insurance upon request. Notwithstanding the foregoing, Biogen may self-insure to the extent that it self-insures for its other products, but at a minimum will
                            self-insure at levels that are consistent with levels customarily maintained against similar risks by similar companies in Biogen&#8217;s industry.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z19fc02a8d495445688f0d546bb9ad7f8">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">9.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>LIMITATION OF CONSEQUENTIAL DAMAGES</u></font>. EXCEPT FOR (a) CLAIMS OF A
                            THIRD PARTY THAT ARE SUBJECT TO INDEMNIFICATION UNDER THIS <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 9</u></font>, (b) CLAIMS ARISING OUT OF A PARTY&#8217;S WILLFUL MISCONDUCT OF THIS AGREEMENT, (c) A
                            PARTY&#8217;S BREACH OF <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 2</u></font>, OR A BREACH OF <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>SECTION 10.4.4(a)</u></font> BY BIOGEN
                            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 OR LOST OR IMPUTED PROFITS OR ROYALTIES, LOST DATA OR COST OF PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES, WHETHER LIABILITY IS ASSERTED
                            IN CONTRACT, TORT (INCLUDING NEGLIGENCE AND STRICT PRODUCT LIABILITY), INDEMNITY OR CONTRIBUTION, AND IRRESPECTIVE OF WHETHER THAT PARTY OR ANY REPRESENTATIVE OF THAT PARTY HAS BEEN ADVISED OF, OR OTHERWISE MIGHT HAVE
                            ANTICIPATED THE POSSIBILITY OF, ANY SUCH LOSS OR DAMAGE<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">.</font></font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">111</font></div>
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            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 10.</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">TERM; TERMINATION</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z28032a12922d4db4a517e3b1c3a92722">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Agreement Term; Expiration</u></font>. This Agreement is effective as of the
                            Effective Date and, unless earlier terminated pursuant to the other provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 10</u></font>, will continue in full force and effect until this
                            Agreement expires as follows:</font></div>
                      </td>
                    </tr>

                </table>
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            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc5a054836c3c4e85930228d163e9d5fe">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.1.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 all Products
                            (or Discontinued Collaboration Product(s)) in such country;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3b8477a2a2384d118bc18c51cbcf8ff9">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.1.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">in its entirety upon the expiration of all payment obligations under this Agreement with respect to all Products (or Discontinued Collaboration Products) in all
                            countries pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.1.1</u></font>;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2d8145d8936341929edcc0feb3962faf">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.1.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">where there are no Collaboration Targets and no Biogen Alternate Modality Targets designated by the expiration of the Research Term as described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.9</u></font>;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6f547b9f719d46699f10385b8981bd33">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.1.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">where there are no Biogen Alternate Modality Targets designated by the expiration of the Research Term as described in <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 1.9</u></font>, and no Development Candidates designated by the expiration of the ASO Development Candidate Identification Term as described in <font style="font-size: 10pt; font-family: 'Times
                              New Roman';"><u>Section 1.10.1(d)</u></font>; and</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2147e25820bb4f32b939d10dd3019448">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.1.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">where there are no Biogen Alternate Modality Targets designated by the expiration of the Research Term as described in <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 1.9</u></font>, and every Option has expired as a result of Biogen not providing Ionis a written notice stating Biogen is exercising such Options and paying Ionis the applicable license fees
                            under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.6</u></font> by the Option Deadline, or as a result of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(g)</u></font>
                            or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.3</u></font>.</font></div>
                      </td>
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            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The period from the Effective Date until the date of expiration of this Agreement pursuant to this <font style="font-size:
                  10pt; font-family: 'Times New Roman';"><u>Section 10.1</u></font> is the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Agreement Term</font>.&#8221;</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">112</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zacded1035c9d4d7d9ab5e734eac3dac0">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination of the Agreement</u></font>.</font></div>
                      </td>
                    </tr>

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            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd7eaf7f3dc7a4c498829887fd2c1713a">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen&#8217;s Termination for Convenience</u></font>.<font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>At any time following payment by Biogen of the upfront fee under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.1</u></font>, subject to
                            <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.1</u></font> below, Biogen will be entitled to terminate this Agreement as a whole, or terminate this Agreement in part with respect to a particular
                            Collaboration Program or Biogen Alternate Modality Target, for convenience by providing 90 days written notice to Ionis of such termination.&#160; </font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z51159c4f7bef40bbb9247e2f968ec455">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination for Failure to Divest Competitive Product</u></font>. If, after the
                            acquisition by a Party of a Third Party that is developing or commercializing an Acquired Competitive Product or an Acquired Competitive Program, such Party does not, by the end of the Collaboration Divestiture Period, divest
                            itself of a Competitive Collaboration Product or Competitive Collaboration Program, as applicable, or terminate the development and commercialization of such Acquired Competitive Product or activities under such Acquired
                            Competitive Program or assign this Agreement to a Third Party that is not itself developing or commercializing a Competitive Collaboration Product or engaged in a Competitive Collaboration Program, as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.5.3</u></font>, then the non-acquiring Party may terminate this Agreement solely with respect to the Collaboration Program(s) affected thereby immediately
                            upon providing written notice to the acquiring Party.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfcd3b7751866427094a891f1faf1b5fe">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination Due to Failure to Obtain HSR Clearance</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z82f0db91d68b4d8ab92802e90ce793f1">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If the Parties make an HSR Filing with respect to a proposed Program under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.7</u></font>,
                            <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.5</u></font> of this Agreement and the HSR Clearance
                            Date has not occurred on or prior to 90 days after the effective date of the latest HSR Filing made by the Parties, this Agreement will terminate solely with respect to the applicable proposed Program (i) at the election of
                            either Party immediately upon notice to the other Party, if the FTC or the DOJ has instituted (or threatened to institute) any action, suit or proceeding including seeking, threatening to seek or obtaining a preliminary
                            injunction under the HSR Act against Biogen and Ionis to enjoin or otherwise prohibit the transactions contemplated by this Agreement related to such proposed Program, or (ii) at the election of either Party, immediately upon
                            notice to the other Party, if the Parties have not resolved any and all objections of the FTC and DOJ as contemplated by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.4(b)</u></font>.
                            Notwithstanding the foregoing, this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.3</u></font> will not apply if an HSR Filing is not required to fully perform this Agreement with respect to a
                            proposed Program, as applicable.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">113</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3c314a11abe647e09a4c5171fbde51df">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If this Agreement is terminated with respect to a Collaboration Program in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section








                                10.2.3(a)</u></font>, then, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">until</font> [***] as follows:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zab6fc8045e834f4fa0483d39f9f7d237">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Ionis [***]; and</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z18d9796846c949919115f8e408c133c5">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Ionis, its Affiliates or the licensee [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 153pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Nothing in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.3(b)</u></font> obligates Ionis
                to (y) [***] or (z) [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z28e7aa0a424042c9953ff33876b0e3a9">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination for Material Breach</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z592b467779724a15a9f2b9816110e8c2">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen&#8217;s Right to Terminate</u></font>. If Biogen believes that Ionis is in
                            material breach of this Agreement (other than with respect to a failure to use Commercially Reasonable Efforts under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 1</u></font>, which is governed by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.5</u></font> below), then Biogen may deliver notice of such material breach to Ionis. If the breach is curable, Ionis will have [***] days to cure such
                            breach. If Ionis fails to cure such breach within the [***] day period, or if the breach is not subject to cure, Biogen may terminate this Agreement with respect to the Neurology Target or Collaboration Program affected by such
                            breach by providing written notice to Ionis. Without limiting the foregoing, breach by a Party of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 2</u></font> of this Agreement constitutes a material
                            breach of this Agreement with respect to the Neurology Target or Collaboration Program affected by such breach.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z46fbcefe6c644eaea0dfad46393ffad2">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Ionis&#8217; Right to Terminate</u></font>. If Ionis believes that Biogen is in
                            material breach of (i) a payment obligation under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font>&#160; or (ii) one or more material provisions of this Agreement where such material breaches
                            have occurred multiple times over the course of at least a [***]-month period (where such material breach is not a single continuous event) demonstrating a pattern of failing to timely comply with Biogen&#8217;s obligations under this
                            Agreement (other than with respect to a failure to use Commercially Reasonable Efforts under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font>, which is governed by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.5</u></font> below), then Ionis may deliver notice of such material breach to Biogen. If the breach is curable, Biogen will have [***] 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 [***] days following such notice). If Biogen fails to cure such breach within the [***] day or [***] day
                            period, as applicable, or if the breach is not subject to cure, Ionis in its sole discretion may terminate this Agreement with respect to the Neurology Target or Collaboration Program affected by such breach by providing written
                            notice thereof to Biogen.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">114</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z738bbd7755fe4be79b76765099ec1e0f">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Remedies for Failure to Use Commercially Reasonable Efforts</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z76bab66aa3a24462b6a181942ef487b9">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Ionis, in Biogen&#8217;s reasonable determination, fails to use Commercially Reasonable Efforts in the activities contemplated in <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>ARTICLE 1</u></font> prior to the date Biogen is granted a license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> (as applicable) with respect to a particular High Interest Target or Collaboration Program, Biogen will notify Ionis and, within [***]
                            days thereafter, Ionis and Biogen 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 Ionis&#8217; use of Commercially
                            Reasonable Efforts in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 1</u></font>. Following such a meeting, if Ionis fails to use Commercially Reasonable Efforts as contemplated by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 1</u></font> with respect to such High Interest Target or Collaboration Program, then subject to <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 10.2.6</u></font> below, Biogen will have the right, at its sole discretion, to (i) terminate this Agreement as it relates to the applicable High Interest Target or Collaboration Program or, (ii) if the
                            breach involves a Collaboration Program prior to the applicable License Effective Date, Biogen may elect to trigger the alternative remedy provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                                10.3</u></font> below as it relates to the applicable Collaboration Program in lieu of terminating this Agreement for such Collaboration Program by providing written notice to Ionis. This <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 10.2.5(a)</u></font> sets forth Biogen&#8217;s sole and exclusive remedies if Ionis fails to use Commercially Reasonable Efforts in the activities contemplated in <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>ARTICLE 1</u></font> prior to the date Biogen is granted a license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> (as applicable).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc9ca81a61c6146bbbf34140410f216ec">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Biogen, in Ionis&#8217; reasonable determination, fails to use Commercially Reasonable Efforts under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section












                                5.1</u></font> with respect to a Collaboration Program, Ionis will notify Biogen and, within [***] days thereafter, Ionis and Biogen 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 Biogen&#8217;s use of Commercially Reasonable Efforts in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font>. Following such
                            a meeting, if Biogen fails to use Commercially Reasonable Efforts with respect to the applicable Collaboration Program as contemplated by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font>,
                            then subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.6</u></font> below, Ionis will have the right, at its sole discretion, to terminate this Agreement as it relates to such
                            Collaboration Program.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za18c2d184f8241468b05b9f94d882aa0">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Disputes Regarding Material Breach</u></font>. Notwithstanding the foregoing,
                            if the Breaching Party in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.5</u></font> 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 [***] day period, the Non-Breaching Party
                            will not have the right to terminate this Agreement in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4</u></font> or <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 10.2.5</u></font>, or the alternative remedy provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.5</u></font>, as applicable, unless and until it has been
                            determined in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font> that this Agreement was materially breached by the Breaching Party and the Breaching Party fails to cure
                            such breach within [***] days following such determination. It is understood and acknowledged that during the pendency of such dispute, all the terms and conditions of this Agreement will remain in effect and the Parties will
                            continue to perform all of their respective obligations hereunder, including satisfying any payment obligations.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">115</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1106b674126d4588b6a4faceaa352f15">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination for Insolvency</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z73ff95692bc94e009358f94a487be671">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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 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.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0ef2583c1aa74823a97c693960b6695a">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z64b28e23f0aa4f3c964e96108940a58b">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.2.8.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination for Patent Challenge</u></font>. Ionis may terminate this Agreement
                            if Biogen (i) commences or otherwise voluntarily determines to participate in 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 (ii) directs, supports or actively assists any other Person 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 and, in each case ((i) or (ii)), within [***] days&#8217; written notice from Ionis, Biogen fails to rescind any and all of such actions, <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-style: italic;">provided however</font> that, nothing in this clause prevents Biogen from taking any of the actions referred to in this clause and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style:
                              italic;">provided further</font> that Ionis will not have the right to terminate if Biogen:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">116</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z38ac3f86845d4dc0995661ba30981ba3">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">takes any such action as described in clause (i) or (ii) above 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, including asserting invalidity as a defense in any court proceeding brought by Ionis asserting infringement of a Licensed Patent; or</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z31ac98b081484655a2291defa8f5dff1">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Acquires a Third Party that has an existing challenge, whether in a court or administrative proceeding, against a Licensed Patent; or</font></div>
                      </td>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z04dca8b30c934cbdb5939f9e4ead94e7">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">licenses a product for which Ionis has an existing challenge, whether in a court or administrative proceeding, against a Licensed Patent.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z60cb2f9c65124deca3ad34a9b247ae3a">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Alternative Remedies to Termination Available to Biogen Prior to </u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>License Effective Date</u></font>. If, prior to the License Effective Date with respect to a particular Collaboration Program Biogen elects to (i)
                            exercise the alternative remedy provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.3</u></font> in lieu of terminating this Agreement for such Collaboration Program by providing
                            written notice of such election to Ionis in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.5(a)</u></font>, or (ii) exercise the Option in accordance with <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>[***]</u></font>, then, in each case, solely with respect to the Collaboration Program giving rise to Biogen&#8217;s exercise of these alternative remedy provisions, this Agreement will
                            continue in full force and effect with the following modifications:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zca5adf44921b4b9eaf8b3f66fc6f9400">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will have no further rights or obligations to Develop the Collaboration Product under the applicable Collaboration Program or participate in the Neurology
                            JRC, the applicable Neurology JDC, JPC or any other subcommittees or working groups established pursuant to this Agreement. Biogen will solely make all decisions that this Agreement would otherwise require or permit the
                            Neurology JRC, the applicable Neurology JDC, JPC or any other subcommittees or working groups, or the Parties collectively, to make; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided,
                              however</font>, that Biogen will not have the right to create any obligations or incur any liabilities for or on behalf of Ionis;</font></div>
                      </td>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">117</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7ffce86ab10b473b867c8aa53a411f94">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">effective as of the date of Biogen&#8217;s notice to Ionis electing the alternative remedy provisions of this <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 10.3</u></font>, Biogen will be deemed for all purposes of this Agreement to have exercised the applicable Option;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2a30d630a1f045b4ab03a06c516ee08a">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen will have and Ionis grants, the exclusive license granted to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font>
                            for the applicable Collaboration Program;</font></div>
                      </td>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zff4111551c444a80a1e6063abdc04e7a">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen may exclude Ionis from all discussions with Regulatory Authorities regarding the applicable Collaboration Products, except to the extent Ionis&#8217; participation
                            is required by a Regulatory Authority or is otherwise reasonably necessary to comply with Applicable Law;</font></div>
                      </td>
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              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z14e958ef9f6e49979f51bf919761a583">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen&#8217;s obligation to make further disclosures of Know-How or other information to Ionis regarding the applicable Collaboration Products pursuant to this Agreement
                            (including pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8</u></font> and <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 5.2.7</u></font>) will terminate, other than reports required by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.14.1</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.4</u></font> (if applicable), and as reasonably required to permit Ionis to perform its obligations under this Agreement; <font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-style: italic;">provided</font> such remedy will not limit or diminish the scope of any licenses granted by Biogen to Ionis under this Agreement;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9311607d870e4aafb2da495b7ac180e5">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will perform its obligations under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>4.8</u></font> with respect to the applicable Collaboration Product within [***] days of Biogen electing to exercise its alternative remedies under this <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 10.3</u></font> or exercising the Option in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>[***]</u></font>, and will provide to Biogen and its
                            Third Party contractors all Know-How, assistance, assignments and other support reasonably requested to assist Biogen in assuming complete responsibility for the Development and Manufacture of the applicable Collaboration
                            Products in an efficient and orderly manner; and</font></div>
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            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5902fdabd90a473c9a8b7ccca9114e96">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(g)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If such Collaboration Program is <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>not</u></font> an ALS Collaboration Program the financial
                            provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font> as they apply to such Collaboration Program will be modified as follows:</font></div>
                      </td>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z31ba1a40714645609c633d9faf59a710">

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                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>[***]Payments</u></font>. Biogen will [***]; and</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdaec62ff15224ba6a8391fec8ce81006">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>License Fee</u></font>. The license fee set forth in <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>Section 6.6</u></font> for the applicable Collaboration Product will be [***]. Such [***] will be due within 90 days after [***] and Biogen&#8217;s [***]. </font></div>
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
                          </font></div>
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"></font></div>
                        <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">The milestone provisions of <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 6.7</u></font> and the royalty provisions
                            of <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 6.10</u></font> will [***].</font></div>
                      </td>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">118</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb90c293c0d4a461187a329bf17f3e26c">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Consequences of Expiration or Termination of the Agreement</u></font>.</font></div>
                      </td>
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                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb3bbac4ce7da4b81b8314961b20b83f9">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>In General</u></font>. If this Agreement expires or is terminated by a Party in
                            accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 10</u></font> at any time and for any reason, the following terms will apply to any Biogen Alternate Modality Product or
                            Collaboration Product (as applicable) that is the subject of such expiration or termination:</font></div>
                      </td>
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                </table>
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            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z504f7ec366614199be70b66ff069a37b">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Return of Information and Materials</u></font>.<font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>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, except to the extent such Confidential Information is necessary or useful to conduct activities for a surviving Product. 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7a69e34ea5204eaca2f4f95e52dc8519">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Accrued Rights</u></font>.<font style="font-size: 10pt; font-family: 'Times New
                              Roman'; 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font> 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4ef1b172df2f4aedac65f61d57115537">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Survival</u></font>. The following provisions of this Agreement will survive
                            the expiration or termination of this Agreement: <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.9</u></font> (End of Research Term), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section












                                1.10.1(d)</u></font> (End of ASO Development Candidate Identification Term), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(f)</u></font> (Failure to Defer or Designate a High Interest
                            Target a Collaboration Target or Biogen Alternate Modality Target), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3</u></font> (Option and Option Deadline) (but only with respect to Biogen&#8217;s
                            transfer obligations thereunder), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.3</u></font> (Effect of Termination on Sublicenses), <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 4.2.2</u></font> (Grant Back to Ionis), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.3</u></font>
                            (Enabling License to Biogen), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.4</u></font> (Enabling License to Ionis),
                            <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.4</u></font> (Licenses to Ionis for Biogen Results), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.5</u></font> (Right to Obtain Direct License from Biogen to Ionis Partner;
                            Sublicensees of Ionis), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8.2</u></font> (Technology Transfer after License
                            Effective Date) (but only to the extent necessary to satisfy the requirements of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.4</u></font>), <font style="font-size: 10pt; font-family: 'Times
                              New Roman';"><u>Section 6.12</u></font> (Reverse Royalty Payments to Biogen for a Discontinued Collaboration Product), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.14.3</u></font> (Records
                            Retention), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.15</u></font> (Audits), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.1</u></font> (Ionis Technology and
                            Biogen Technology), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font> (Agreement Technology), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.4</u></font>
                            (Disclaimer), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 9</u></font> (Indemnification; Insurance), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.3(b)</u></font>,
                            <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.7</u></font> (Termination for Insolvency), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4</u></font> (Consequences
                            of Expiration or Termination of the Agreement) (except <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.5</u></font> (Remedies Available to Biogen for Ionis&#8217; Material Breach After License Effective
                            Date)), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 11</u></font> (Confidentiality), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 12</u></font> (Miscellaneous) and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 1</u></font> (Definitions) (to the extent definitions are embodied in the foregoing listed Articles and Sections).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">119</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc4559092e66141d183514a30411347a6">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Natural Expiration</u></font>. If this Agreement expires in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.1.1</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.1.2</u></font>, the following terms will apply to any
                            Biogen Alternate Modality Product or Collaboration Product (as applicable) that is the subject of such expiration:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6f79a1f4db6e4508a72634b35bda2e47">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Perpetual, Royalty-Free Non-Exclusive License</u></font>. If Biogen has been
                            granted a license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> (as
                            applicable) for a particular Product, then upon expiration of the Biogen Alternate Modality Royalty Period or Reduced Royalty Period, as the case may be, in all countries in which the applicable Products are being or have been
                            sold, Ionis will and hereby does grant to Biogen a perpetual, non-exclusive, worldwide, royalty-free, fully paid-up, sublicensable license under the Ionis Know-How to Manufacture, Develop and Commercialize the applicable
                            Product.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za251b2c87c534503a68f8c1993909871">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination </u></font><font style="font-size: 10pt; font-family: 'Times New
                              Roman'; font-weight: bold;"><u>Prior to License </u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Effective Date</u></font>. If this Agreement expires or is terminated by a Party
                            in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 10</u></font> before the License Effective Date for a particular Program, then, in addition to the terms set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.1</u></font>, the following terms will apply to each Product, Neurology Target, High Interest Target or Collaboration Program that is the subject of such
                            expiration or termination:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfdf68d33fc23475486222369317397df">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen&#8217;s right to designate High Interest Targets as Collaboration Targets or Biogen Alternate Modality Targets under this Agreement will expire and Ionis will be
                            free to Develop and Commercialize the applicable Product (and any other applicable Compounds) on its own or with a Third Party.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">120</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z484a851aac754895b416467f86657bc6">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen&#8217;s Option under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1</u></font> will expire and Ionis will be free to Develop and
                            Commercialize the applicable Collaboration Product (and any other applicable Compounds) on its own or with a Third Party.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z86809ee31f8846c384c34ef73c856af1">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Neither Party will have any further obligations under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1</u></font> of this Agreement
                            with respect to the terminated Neurology Targets and Collaboration Program(s).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf73d061f2c604d5292506dd7c9866fc0">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">To the extent requested by Ionis, Biogen will promptly (i) assign to Ionis any manufacturing agreements with a CMO identified by Ionis to which Biogen is a party,
                            solely to the extent such manufacturing agreements relate to the terminated Collaboration Program and (ii) transfer to Ionis all data, results and information (including Biogen&#8217;s Confidential Information and any regulatory
                            documentation (including drafts)) related to the testing and Clinical Studies under the terminated Collaboration Program(s) in the possession of Biogen and its contractors to the extent such data, results and information were
                            generated by or on behalf of Biogen under this Agreement; and Ionis will pay all out-of-pocket direct Third Party costs and expenses in transferring such data, results and information together with Biogen&#8217;s FTE Cost in
                            transferring such data, results and information.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z54934f1aede64c3fa675d69aa5bc501d">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Biogen terminates this Agreement for convenience with respect to a Collaboration Program after the 30<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup> day following Biogen&#8217;s receipt of the Development Candidate Data Package for such Collaboration Program, but prior to the License Effective Date for such Collaboration Program, then Biogen will
                            [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z191ac3d2a6b44f09939f7bce8e0fdcea">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Except as explicitly set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.1(a)</u></font>, <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 10.4.1(b)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.1(c)</u></font>, Biogen will have no further rights and Ionis will have no
                            further obligations with respect to each terminated Collaboration Program.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zab4bf3662b184cc896cc767660d0dbd2">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(g)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Biogen terminates this Agreement for convenience with respect to a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS
                            Collaboration Program, then solely with respect to such Collaboration Program:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z13eb890f699b4ae8929694431cf17323">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen will, and does hereby, grant to Ionis a sublicensable, worldwide, exclusive license or sublicense, as the case may be, to all Biogen Technology Controlled by
                            Biogen as of the date of such reversion that Covers the applicable Discontinued Collaboration Product(s) solely as necessary to Develop, make, have made, use, sell, offer for sale, have sold, import and otherwise Commercialize
                            the applicable Discontinued Collaboration Product(s) in the Field (such license will be sublicensable by Ionis in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">mutatis mutandis</font>); and</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">121</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za689d8720cdc4715853dfbdbc68fccdb">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Within [***] days following the date of the termination, Biogen will assign, and hereby does assign, to Ionis all of Biogen&#8217;s right, title and interest in and to
                            all Regulatory Materials, including any IND and orphan drug designation that relate to the applicable Discontinued Collaboration Product(s), <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided








                              that</font>, (A) notwithstanding the foregoing, and subject to the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1</u></font>, the Parties acknowledge that Biogen shall be permitted
                            to use excerpts or portions of any such assigned Regulatory Materials in any other regulatory submissions, notifications, registrations, approvals and/or other filings and correspondence made to or with a Regulatory Authority in
                            any country or jurisdiction related to products under the Ionis/Biogen Additional Agreements or products that do not include an Oligonucleotide (other than any Gene-Editing Product or messenger RNA) as an active pharmaceutical
                            ingredient, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, further</font> that, for such products that do not include such an Oligonucleotide as an active pharmaceutical ingredient,
                            such excerpts or portions shall not include any Confidential Information of Ionis, and (B) for clarity, such assignment of Biogen&#8217;s right, title and interest in and to such Regulatory Materials shall not include the assignment
                            of any Know-How (including any data) contained therein.&#160; If Biogen intends to use any excerpt or portion of any such assigned Regulatory Materials in accordance with clause (A) of the preceding sentence, Biogen shall, at least
                            [***] days in advance of the anticipated submission of such excerpt or portion to a Regulatory Authority, notify Ionis of such intent and provide to Ionis a copy of such proposed excerpt or portion for review and comment.&#160; The
                            Parties shall discuss in good faith any comments of Ionis with respect to such proposed excerpt or portion prior to submission thereof.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z29564ff93e0042c1a92cea3a89530291">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(h)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Biogen terminates this Agreement for convenience with respect to an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, then solely
                            with respect to such Collaboration Program:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">122</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc131b2ba1dc04a3f9d0346e968e268a4">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen will, and does hereby, grant to Ionis a sublicensable, worldwide, exclusive license or sublicense, as the case may be, to all Biogen Technology Controlled by
                            Biogen as of the date of such reversion that Covers the applicable Discontinued Collaboration Product(s) solely as necessary to Develop, make, have made, use, sell, offer for sale, have sold, import and otherwise Commercialize
                            the applicable Discontinued Collaboration Product(s) in the Field (such license will be sublicensable by Ionis in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">mutatis mutandis</font>);</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4f362f42cdcc41d2917285482dbd181a">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Within [***] days following the date of the termination, Biogen will transfer to Ionis for use with respect to the Development and Commercialization of the
                            applicable Discontinued Collaboration Product(s), any Know-How, data, results and copies of Regulatory Materials in the possession of Biogen as of the date of such reversion to the extent related to such Discontinued
                            Collaboration Product(s), and any other information or material specified in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8</u></font>,
                            <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that</font>, for the avoidance of doubt, as between the Parties, title to any intellectual property that is Biogen Technology within any
                            of the foregoing will remain with Biogen subject to the license granted to Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.3(h)(i)</u></font>;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za5203227d2c44138a66159434b3ebb9b">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Within [***] days following the date of the termination, Biogen will assign, and hereby does assign, to Ionis all of Biogen&#8217;s right, title and interest in and to
                            all Regulatory Materials, including any IND and orphan drug designation that relate to the applicable Discontinued Collaboration Product(s), <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided








                              that</font>, (x) notwithstanding the foregoing, and subject to the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1</u></font>, the Parties acknowledge that Biogen shall be permitted
                            to use excerpts or portions of any such assigned Regulatory Materials in any other regulatory submissions, notifications, registrations, approvals and/or other filings and correspondence made to or with a Regulatory Authority in
                            any country or jurisdiction related to products under the Ionis/Biogen Additional Agreements or products that do not include an Oligonucleotide (other than any Gene-Editing Product or messenger RNA) as an active pharmaceutical
                            ingredient, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, further</font> that, for such products that do not include such an Oligonucleotide as an active pharmaceutical ingredient,
                            such excerpts or portions shall not include any Confidential Information of Ionis, and (y) for clarity, such assignment of Biogen&#8217;s right, title and interest in and to such Regulatory Materials shall not include the assignment
                            of any Know-How (including any data) contained therein.&#160; If Biogen intends to use any excerpt or portion of any such assigned Regulatory Materials in accordance with clause (x) of the preceding sentence, Biogen shall, at least
                            [***] days in advance of the anticipated submission of such excerpt or portion to a Regulatory Authority, notify Ionis of such intent and provide to Ionis a copy of such proposed excerpt or portion for review and comment.&#160; The
                            Parties shall discuss in good faith any comments of Ionis with respect to such proposed excerpt or portion prior to submission thereof; and</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">123</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze5543e8b831a4f0289c185739eec365c">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iv)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">To the extent requested by Ionis, Biogen will promptly assign to Ionis any manufacturing agreements solely to the extent related to the applicable Discontinued
                            Collaboration Products and identified by Ionis to which Biogen is a party.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3f9cb442476e45788347c18cfbdf9ac8">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination After License </u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;"><u>Effective Date</u></font>. If this Agreement is terminated by a Party in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 10</u></font>
                            after the License Effective Date for a particular Product, then, in addition to the terms set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.1</u></font>, the following terms will apply
                            to any Product or Collaboration Program that is the subject of such termination:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd4aa719107d94fe59b2600705ce9a6f1">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The applicable licenses granted by Ionis to Biogen under this Agreement will terminate. Biogen, its Affiliates and Sublicensees will cease selling the applicable
                            Products, unless Ionis elects to have Biogen continue to sell the applicable Products as part of the Transition Services to the extent provided in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.6</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z46fc0b22877c4f75ab207e09124f6162">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Neither Party will have any further obligations under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1</u></font> of this Agreement
                            with respect to the terminated Product, Neurology Target and Collaboration Program(s).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd67d61399e0a4b2784103baa2fb48187">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Except as explicitly set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.1(a)</u></font>, Biogen will have no further
                            rights and Ionis will have no further obligations with respect to the terminated Product, Neurology Target and Collaboration Program(s).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6fefe8e980b84ff9aa795050f26775f9">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If (i) Biogen terminates the Agreement under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.1</u></font> (Biogen&#8217;s Termination for
                            Convenience) or (ii) Ionis terminates this Agreement under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4(b)</u></font> (Ionis&#8217; Right to Terminate) or <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 10.2.5</u></font> (Remedies for Failure to Use Commercially Reasonable Efforts), then the following additional terms will also apply solely with respect to the terminated Products
                            and/or Collaboration Program(s):</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">124</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd7809fc17e794730889510bf5ce79dd8">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen will, and does hereby, grant to Ionis a sublicensable, worldwide, exclusive license or sublicense, as the case may be, to all Biogen Technology Controlled by
                            Biogen as of the date of such reversion that Covers the applicable Discontinued Collaboration Product(s) solely as necessary to Develop, make, have made, use, sell, offer for sale, have sold, import and otherwise Commercialize
                            the applicable Discontinued Collaboration Product(s) in the Field (such license will be sublicensable by Ionis in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">mutatis mutandis</font>);</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z22e29e1c8d1a488e97cd4ec398f81e1a">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Within [***] days following the date of the termination, Biogen will assign back to Ionis any Product-Specific Patent Rights and Ionis&#8217; interest in any Program
                            Patents that relate to the applicable Biogen Alternate Modality Product(s) and/or Discontinued Collaboration Product(s) previously assigned by Ionis to Biogen under this Agreement;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9ea49f79de99493fb2808b3a7fa8e55c">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Within [***] days following the date of the termination, Biogen will transfer to Ionis solely for use with respect to the Development and Commercialization of the
                            applicable Discontinued Collaboration Product(s), any Know-How, data, results and copies of Regulatory Materials in the possession of Biogen as of the date of such reversion to the extent related to such Discontinued
                            Collaboration Product(s), and any other information or material specified in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8</u></font>,
                            <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that</font>, for the avoidance of doubt, as between the Parties, title to any intellectual property that is Biogen Technology within any
                            of the foregoing will remain with Biogen subject to the license granted to Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.4(d)(i)</u></font>, except as otherwise provided in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.4(d)(iv)</u></font> below;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4aacd6f98b6e438980f11389d0c02fa3">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iv)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Within [***] days following the date of the termination, Biogen will assign, and hereby does assign, to Ionis all of Biogen&#8217;s right, title and interest in and to
                            all Regulatory Materials, including any NDA, IND and orphan drug designation that relate to the applicable terminated Product(s), <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided that</font>,
                            (x) notwithstanding the foregoing, and subject to the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1</u></font>, the Parties acknowledge that Biogen shall be permitted to use
                            excerpts or portions of any such assigned Regulatory Materials in any other regulatory submissions, notifications, registrations, approvals and/or other filings and correspondence made to or with a Regulatory Authority in any
                            country or jurisdiction related to&#160; products under the Ionis/Biogen Additional Agreements or products that do not include an Oligonucleotide as an active pharmaceutical ingredient, <font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-style: italic;">provided, further</font> that, for such products that do not include an Oligonucleotide as an active pharmaceutical ingredient, such excerpts or portions shall not include any
                            Confidential Information of Ionis, and (y) for clarity, such assignment of Biogen&#8217;s right, title and interest in and to such Regulatory Materials shall not include the assignment of any Know-How (including any data) contained
                            therein.&#160; If Biogen intends to use any excerpt or portion of any such assigned Regulatory Materials in accordance with clause (x) of the preceding sentence, Biogen shall, at least [***] days in advance of the anticipated
                            submission of such excerpt or portion to a Regulatory Authority, notify Ionis of such intent and provide to Ionis a copy of such proposed excerpt or portion for review and comment.&#160; The Parties shall discuss in good faith any
                            comments of Ionis with respect to such proposed excerpt or portion prior to submission thereof;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">125</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze937f50944904c0a8ea493912906c803">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(v)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen will, and does hereby, exclusively license to Ionis any trademarks that are specific to a Discontinued Collaboration Product(s) solely for use with such
                            Discontinued Collaboration Product(s), in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.6</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style:
                              italic;">mutatis mutandis</font>; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, in no event will Biogen have any obligation to license to Ionis any trademarks
                            used by Biogen both in connection with the Product and in connection with the sale of any other product or service, including any BIOGEN- or BIOGEN-formative marks;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z98dc9aca05e3452d9ed07936456e35b7">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(vi)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will control and be responsible for all aspects of the Prosecution and Maintenance of all Jointly-Owned Program Patents arising from the terminated Product
                            and/or Collaboration Program, and Biogen will provide Ionis with (and will instruct its counsel to provide Ionis with) all of the information and records in Biogen&#8217;s and its counsel&#8217;s possession related to the Prosecution and
                            Maintenance of such Jointly-Owned Program Patents; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, if Ionis intends to abandon any such Jointly-Owned Program Patents
                            without first filing a continuation or substitution, then Ionis will notify Biogen of such intention at least [***] days before such Patent Right will become abandoned, and Biogen will have the right, but not the obligation, to
                            assume responsibility for the Prosecution and Maintenance thereof at its own expense with counsel of its own choice; and</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1a642735ed174444a6d21055f79e96b9">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(vii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will have the obligation to pay royalties to Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.12</u></font> with
                            respect to the applicable Discontinued Collaboration Product(s).&#160; Such payments will be governed by the financial provisions in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.14</u></font>, and the
                            definition of Net Sales will apply to sales of Discontinued Collaboration Product(s) by Ionis, in each case <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">mutatis mutandis</font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">126</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z18e8c46cf915490aada755723750b717">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">With respect to Discontinued Collaboration Products, if Ionis terminates this Agreement due to Biogen&#8217;s material breach or Biogen terminates this Agreement for
                            convenience, upon Ionis&#8217; written request pursuant to a mutually agreed supply agreement, Biogen will sell to Ionis any bulk API, Clinical Supplies and Finished Drug Product in Biogen&#8217;s possession at the time of such termination,
                            at a price equal to [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z609b42810873419aa17d70d1773d088a">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">To the extent requested by Ionis, Biogen will promptly assign to Ionis any manufacturing agreements solely to the extent related to the applicable Discontinued
                            Collaboration Products and identified by Ionis to which Biogen is a party.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z474d9318defe400e9f30032e3a0df70d">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(g)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Biogen under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.1</u></font> or <font style="font-size: 10pt; font-family: 'Times
                              New Roman';"><u>Section 10.2.2</u></font> voluntarily terminates its license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> with respect to a High Interest Target Biogen
                            designated as a Biogen Alternate Modality Target then <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(f)</u></font> will apply.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z60df5643d07b452e9fd9f0b91053b0a9">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Remedies Available to Biogen for Ionis&#8217; Material Breach After </u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>License Effective Date</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze4ddc549ff93450bb0f702dbc4be872c">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Termination of Committees and Information Sharing</u></font>. If, after the
                            License Effective Date with respect to a particular Collaboration Program, Ionis materially breaches this Agreement and fails to cure such breach within the time periods set forth under <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 10.2.4(a)</u></font>, and Biogen does not wish to terminate this Agreement in its entirety (an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                              font-style: italic;">Ionis Breach Event</font>&#8221;), then, in addition to any other remedies Biogen may have under this Agreement or otherwise, Biogen will have the right to do any or all of the following in Biogen&#8217;s discretion
                            solely with respect to the Collaboration Programs that are the subject of the Ionis Breach Event:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6113dab81c284719b0fd8ffbf2b32b91">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Terminate Ionis&#8217; right to participate in the CSC, Neurology JRC, the applicable Neurology JDC, JPC and any other subcommittees or working groups established
                            pursuant to this Agreement;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9a2a851637c84f239027c22db3d53135">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Terminate Ionis&#8217; participation in any ongoing research and development programs under the applicable Collaboration Program and Biogen&#8217;s funding obligations
                            associated therewith;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">127</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9d35938ff8cc439585df7d0ae7eae3ab">

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                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Solely make all decisions required or permitted to be made by such committees or the Parties collectively under this Agreement in connection with the Development
                            and Commercialization of the applicable Collaboration Product; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Biogen will not have the right to create any
                            obligations or incur any liabilities for or on behalf of Ionis;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0eab8a116df3483da73e12874af7ae39">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iv)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Exclude Ionis from all discussions with Regulatory Authorities regarding applicable Products, <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-style: italic;">except</font> to the extent Ionis&#8217; participation is required by a Regulatory Authority or is otherwise reasonably necessary to comply with Applicable Law;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z21310f1cbb874de9840295f19df1f067">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(v)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Terminate Biogen&#8217;s obligation to make further disclosures of Know-How or other information to Ionis pursuant to this Agreement related to the applicable
                            Collaboration Products, including pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.2.7</u></font>, other than reports required by <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.14.1</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.4</u></font> (if applicable), and as reasonably required to permit Ionis to perform its obligations under this Agreement; <font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-style: italic;">provided</font> such remedy will not limit or diminish the scope of any licenses granted by Biogen to Ionis under this Agreement; and</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd938ca9bf5d34d56817f659122646af5">

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                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(vi)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Ionis has not completed the Development activities that are its responsibility under the applicable ASO Development Candidate Identification Plan and Initial
                            Development Plan, then Biogen may, but will not be obligated to, assume all responsibility for all such Development activities that would have otherwise been Ionis&#8217; responsibility under this Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 117pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will cooperate with the foregoing and provide to Biogen and its Third Party contractors all Know-How, assistance,
                assignments and other support reasonably requested to assist Biogen in assuming complete responsibility for the Development and Manufacture of the applicable Products in an efficient and orderly manner.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">128</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za01c9ccc4bc543e9a74d466501238ce0">

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                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen&#8217;s Right of Setoff</u></font>. If there is [***] and Biogen does not wish
                            to [***], then, in addition to any other remedies Biogen may have under this Agreement or otherwise, Biogen may setoff against any amounts owed to Ionis pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE












                                6</u></font> (Financial Provisions) <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">solely </font>with respect to the Collaboration Program that is the subject of the Ionis Breach Event
                            [***] (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Setoff Amount</font>&#8221;). If Biogen exercises its setoff right under this <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 10.4.5(b)</u></font>, Biogen will provide Ionis with a written certificate, signed by Biogen&#8217;s Chief Financial Officer, certifying that the amount setoff by Biogen represents [***].
                            Notwithstanding the foregoing, if Ionis notifies Biogen in writing (a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Setoff Dispute Notice</font>&#8221;) that it disputes
                            Biogen&#8217;s assertion that Ionis is in material breach of this Agreement or the amount setoff by Biogen (a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Setoff Dispute</font>&#8221;),







                            then (i) both Parties will participate in the dispute resolution process set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u> 10.4.5(b)</u></font>, and (ii) pending the Parties' agreement regarding the appropriate setoff (if any) or a determination by the Advisory Panel of the proper amount that Biogen may setoff
                            (if any) in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 10.4.5(b)</u></font>,
                            Biogen will pay the Setoff Amount into an interest-bearing escrow account established for the purpose at a bank. If the Parties cannot settle their dispute by mutual agreement, then, in accordance with <font style="font-size:
                              10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 10.4.5(b)</u></font> the Advisory Panel will determine (1) the amount
                            (if any) that Biogen may setoff against future payments <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">solely </font>with respect to the Collaboration Program that is the subject of the
                            Ionis Breach Event to Ionis going forward, and (2) whether any portion of the escrow account should be released to Ionis or returned to Biogen, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>
                            that any decision or determination by the Advisory Panel (a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Panel Decision</font>&#8221;) will not be treated as an arbitral award
                            but will be binding on the Parties until and unless a court of competent jurisdiction (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Trial Court</font>&#8221;) has
                            determined in a judgment regarding some or all of the issues decided in the Panel Decision, and in any Action contemplated by the next sentence hereof the Trial Court will determine the facts and the law <font style="font-size:
                              10pt; font-family: 'Times New Roman'; font-style: italic;">de novo</font>, and will give a Panel Decision only such persuasive effect, if any, that after review of all of the facts and the law presented to the Trial Court by
                            the Parties, the Trial Court deems appropriate, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that the escrow agent will comply with a Panel Decision that determines that any
                            portion of the escrow account should be released to Ionis or returned to Biogen. If it is determined in a judgment by the Trial Court that Ionis owes Biogen any damages, then, during the pendency of any appeal of the Trial
                            Court&#8217;s decision (or, if the Trial Court&#8217;s decision is not appealed, until Biogen recoups such amount), Biogen may setoff against any future payments <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style:
                              italic;">solely </font>with respect to the Collaboration Programs that are the subject of the Ionis Breach Event to Ionis under this Agreement the amount of any such damages not paid by Ionis.&#160; If it is determined in a Trial
                            Court that Biogen has setoff an amount that exceeds the amount of losses, damages and expenses actually incurred by Biogen as a result of Ionis&#8217; breach of this Agreement, then Biogen will promptly pay Ionis the amount of such
                            excess, plus interest on such amount as provided for in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.17</u></font> (Interest on Late Payments), with interest accruing from the time Biogen applied
                            such excess setoff.&#160; If, with respect to a Setoff Dispute, Ionis provides a Setoff Dispute Notice to Biogen and Biogen fails to do any of the following: (X) appoint a member of the Advisory Panel to the extent required in
                            Section 2 of <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 10.4.5(b)</u></font>; (Y) meet with
                            the Advisory Panel as required in Section 3 of <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>
                                10.4.5(b);</u></font> or (Z) pay the Setoff Amount into an interest-bearing escrow account established for the purpose at a bank, then Biogen will forfeit its right to set off under this <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 10.4.5(b)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u> 10.4.5(b)</u></font> with respect to any and all Setoff Disputes.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">129</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z10f3b4d10dd14372ada7937869c5ed9c">

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                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">10.4.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Transition Services</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zbafbc6b91fc54219a3393d9135dd8b05">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In the case where (i) Biogen terminates the Agreement under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.1</u></font> (Biogen&#8217;s
                            Termination for Convenience) or (ii) Ionis terminates this Agreement under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.4(b)</u></font> (Ionis&#8217; Right to Terminate) or <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>Section 10.2.5</u></font> (Remedies for Failure to Use Commercially Reasonable Efforts) with respect to one or more Products, the terms of this <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>10.4.6</u></font>&#160;shall apply.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8169cca40ca4444ba5eb6649b2ad7aef">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In such event, the Parties wish to provide a mechanism to ensure that patients who were being treated with the applicable Product prior to such termination or who
                            desire access to such Product can continue to have access to such Product until the regulatory and commercial responsibilities for the Product are transitioned from Biogen to Ionis following the termination of the applicable
                            Product. As such, Ionis may request Biogen perform transition services as listed on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u> 10.4.6</u></font> and such other transition services that the Parties mutually agree in writing to (i) provide patients with continued access to the applicable Products, (ii) following the
                            termination of this Agreement with respect to the applicable Product, transition the responsibilities under all Approvals and ongoing Clinical Studies for the applicable Product to Ionis or its designee and (iii) following
                            termination of this Agreement with respect to the applicable Collaboration Target, transition the then-current supply process and responsibilities for the Product to Ionis or its designee (collectively, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Transition Services</font>&#8221;). Subject to the Parties agreeing on a transition plan as described in <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>10.4.6(c)</u></font>, Biogen will perform such Transition Services using reasonable efforts for a period
                            not to exceed [***] months from the termination date; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that Biogen and Ionis may mutually agree to conduct the Transition
                            Services for a longer period of time. Notwithstanding the provision of the Transition Services under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>10.4.6(b)</u></font>, Ionis shall not conduct activities with respect to any Discontinued Products to the extent prohibited by&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE







                                2</u></font>&#160;of this Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z36dcec5827cd4d6db080141c3eac4dca">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis may elect to have Biogen perform the Transition Services by providing written notice to Biogen no later than the earlier of (i) [***] days following the
                            effective date of the termination and (ii) [***] days following written notice by Biogen to Ionis asking Ionis to confirm if Ionis wishes to have Biogen perform the Transition Services (provided Biogen did not send such a notice
                            earlier than [***] days following the effective date of the termination). If Ionis requests Transition Services, then Ionis shall propose a transition plan setting forth the Transition Services to be performed by Biogen,
                            including delivery and transition dates consistent with those set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u> 10.4.6</u></font>, and, for a period of [***] days after such request, the Parties will use good faith efforts to negotiate a mutually agreeable version of such transition plan.&#160; In
                            addition, the Parties will, within [***] days after such request, establish a transition committee consisting of at least each Party&#8217;s Alliance Managers, a representative from each Party&#8217;s CMC group who was responsible for the
                            Product prior to the termination, and up to two additional representatives from each Party who are from other relevant functional groups to facilitate a smooth transition. While Biogen is providing Transition Services, Biogen
                            and Ionis will mutually agree on talking points and a communication plan to customers, specialty pharmacies, physicians, Regulatory Authorities, patient advocacy groups, and clinical study investigators, and Biogen will make all
                            such communication to such entities in accordance with the mutually agreed talking points.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0eeb5c6f4dd34abb9f6f6f61d3199d2c">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will pay Biogen for the Transition Services at [***] to perform the Transition Services, calculated [***]. In addition, Ionis will reimburse [***] to perform
                            the Transition Services. Ionis will own all revenue derived from the Product after the termination date and Biogen will remit all such revenues to Ionis no later than the [***] day following the end of the month in which such
                            revenue was received.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfc69bdb4fe0041c89c8474ea5e862c85">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis or its designee will be sufficiently prepared to accept the transition of Development, Manufacturing and Commercialization activities with respect to the
                            Products to Ionis or such designee on the timelines set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times
                              New Roman';"><u> 10.4.6</u></font> for the Transition Services.&#160; Biogen will have no liability under this Agreement with respect to a failure of or delay in the Transition Services to the extent caused by any failure or delay
                            by Ionis or its designee in accepting the transition of Development, Manufacturing and Commercialization activities with respect to the Products.&#160; In the event that Biogen encounters any delays beyond Biogen&#8217;s reasonable
                            control, the Parties shall discuss in good faith and agree upon extended timelines for completion of the Transition Services.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
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            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 11.</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">CONFIDENTIALITY</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb8527739d00f49759c8628dac22b6ca3">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Confidentiality; Exceptions</u></font>. Except to the extent expressly
                            authorized by this Agreement or otherwise agreed in writing, the Parties agree that, during the Agreement Term and for five years thereafter, the receiving Party (the &#8220;<font style="font-size: 10pt; font-family: 'Times New
                              Roman'; 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 or 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-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Confidential Information</font>&#8221;).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb2f2b3d1f5ac434b8a047789f787d6f2">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Prior Confidentiality Agreement Superseded</u></font>. As of the Effective
                            Date, this Agreement supersedes the Confidential Disclosure Agreement executed by Ionis and Biogen on February 28, 2011 (including any and all amendments thereto). All information exchanged between the Parties under such
                            Confidential Disclosure Agreement will be deemed Confidential Information hereunder and will be subject to the terms of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 11</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za63975294079479e81a250f9ed09b2a1">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Authorized Disclosure</u></font>. 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>
                            that Confidential Information may be disclosed by a Receiving Party to a governmental entity or agency without requiring such entity or agency to enter into a confidentiality agreement; (ii) to the extent reasonably necessary to
                            file or prosecute patent, copyright and trademark applications (subject to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4</u></font> below), complying with applicable governmental regulations,
                            obtaining Approvals, conducting Pre-Clinical Studies or Clinical Studies, marketing the 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-size: 10pt; font-family: 'Times New Roman'; 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>
            </div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">132</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3518269cf8284b088769876a6b6b4e3b">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Press Release; Publications; Disclosure of Agreement</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2a29111de13140668d129eb018226430">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Appointment of a Communications Lead</u></font>. Prior to the Initiation of
                            each Clinical Study under the Initial Development Plan for any Collaboration Program for which Biogen has not yet been granted a license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font>
                            or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> (as applicable) with respect to a Product, the Neurology JDC for such Collaboration Program shall appoint one of the Parties as
                            the communications lead to take the lead role in drafting, coordinating and facilitating the public disclosure of data and results arising from such Clinical Study (the &#8220;<font style="font-size: 10pt; font-family: 'Times New
                              Roman'; font-weight: bold; font-style: italic;">Communications Lead</font>&#8221;); <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that (a) if a single Party is the
                            IND-holder and sponsor of the Clinical Study, and is responsible for the conduct of the Clinical Study, then that Party shall automatically be deemed to be the Communications Lead and (b) if the applicable Neurology JDC cannot
                            agree upon the designation of a Communications Lead, such matter shall be submitted to the CSC for resolution. The Communications Lead shall be responsible for drafting the initial publication and for coordinating and
                            facilitating the disclosure activities for such Clinical Study as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections 11.4.5</u></font> and <font style="font-size: 10pt; font-family: 'Times
                              New Roman';"><u>11.4.6</u></font>; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that if, after having worked together in good faith, the Communications Lead and
                            the other Party cannot agree on a matter related to the public disclosure of data and results arising from such a Clinical Study, then, subject to and without limiting <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Sections 11.4.5</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>11.4.6</u></font>, (i) prior to the License Effective Date for such Collaboration Program, Ionis will have final
                            decision-making authority regarding such matter, and (ii) after the License Effective Date for such Collaboration Program, Biogen will have final decision-making authority regarding such matter.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1b5e1dc5187a4c4a856f8e66eca4d45c">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Public Announcements</u></font>. On or promptly after the Effective Date, the
                            Parties will jointly issue a public announcement of the execution of this Agreement in form and substance mutually agreed 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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4</u></font>, neither Party nor such Party&#8217;s Affiliates will make any public announcements,
                            press releases or other public disclosures concerning this Agreement or the terms or the subject matter hereof without the prior written consent of the other, which will not be unreasonably withheld, conditioned or delayed.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1fcec0ed6b5b4068bbdec5fd7d7346fa">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Use of Name</u></font>.<font style="font-size: 10pt; font-family: 'Times New
                              Roman'; font-weight: bold;">&#160;</font>Except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.11</u></font>, 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>
            </div>
            <div><br>
            </div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z53986fa2bdf24c15bc233276ce13b97a">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Notice of Significant Events</u></font>. Each party will immediately notify
                            (and provide as much advance notice as possible, but at a minimum two Business Days advance notice to) the other Party of any event materially related to a Product (including in such notice any disclosure of starting/stopping of
                            a Clinical Study, clinical data or results, material regulatory discussions, filings, Approval or Biogen&#8217;s sales projections) so the Parties may analyze the need for or desirability of publicly disclosing or reporting such
                            event.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc5247524e99c4a428ea9b1b53974d644">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Prior to License Grant</u></font>. Prior to the date Biogen has been granted a
                            license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> (as applicable) with
                            respect to a Product, such Product is the sole property of Ionis and, subject to any communication plan for such Product mutually agreed to by the Parties in accordance with <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 1.10.2(d)</u></font> and to the provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.5</u></font> and <font style="font-size: 10pt; font-family: 'Times New
                              Roman';"><u>Section 11.4.7</u></font>, Ionis will have the sole right to issue press releases, publish, present or otherwise disclose the progress and results regarding such Product to the public, which shall be consistent
                            with its practice with its other compounds and products; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-style: italic;">that</font>, with respect to any proposed press release or other similar public communication by Ionis disclosing regulatory discussions, the efficacy or safety data or clinical results related to such
                            Product, (i) Ionis will submit such proposed communication to Biogen for review at least two Business Days in advance of such proposed public disclosure, (ii) Biogen will have the right to review and recommend changes to such
                            communication, and (iii) Ionis will in good faith consider any changes that are timely recommended by Biogen; and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">further</font> that, if Biogen conducted or co-conducted a Clinical Study that is the subject of such public announcement, press release or other
                            public disclosure, then any such public announcement, press release or other public disclosure shall be jointly issued by the Parties (unless Biogen expressly waives in writing its right to jointly issue such public
                            announcement, press release or other public disclosure). If Biogen desires to make any public announcement, issue a press release or make any other public disclosure with respect to a Clinical Study that was conducted or
                            co-conducted by Biogen prior to the date Biogen has been granted a license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 4.1.1(b)</u></font> (as applicable) with respect to a Product, Biogen shall so notify Ionis and shall provide Ionis with a draft thereof at least two Business Days prior to the proposed
                            publication thereof. Ionis may review and provide comments to Biogen and the Parties shall discuss in good faith any such comments and seek to mutually agree on a final version of such proposed public announcement, press release
                            or other public disclosure. Notwithstanding the foregoing, Ionis shall, pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.5</u></font>, retain final decision-making authority over
                            (x) whether such proposed public announcement, press release or other public disclosure shall be issued or made, and (y) the content thereof, and in no event shall Biogen issue any such public announcement, press release or
                            other public disclosure under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.5</u></font> except in the final version approved by Ionis.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd390924441174f40ae7dd7eb495028c5">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>After License Grant</u></font>. After the date Biogen has been granted a
                            license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> (as applicable) with
                            respect to a Product, subject to the provisions of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.6</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                                11.4.7</u></font>, Biogen will have the sole right to issue press releases, publish, present or otherwise disclose the progress and results regarding such Product to the public, which shall be consistent with its practice
                            with its other compounds and products; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that with respect to any proposed press release or other similar public communication by
                            Biogen disclosing regulatory discussions, the efficacy or safety data or results related to such Product or Biogen&#8217;s sales projections, (a) Biogen will submit such proposed communication to Ionis for review at least two Business
                            Days in advance of such proposed public disclosure, (b) Ionis will have the right to review and recommend changes to such communication and (c) Biogen will in good faith consider any changes that are timely recommended by Ionis;
                            and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">further</font> that, if Ionis conducted
                            or co-conducted a Clinical Study that is the subject of such public announcement, press release or other public disclosure, then any such public announcement, press release or other public disclosure shall be jointly issued by
                            the Parties (unless Ionis expressly waives in writing its right to jointly issue such public announcement, press release or other public disclosure). If Ionis desires to make any public announcement, issue a press release or
                            make any other public disclosure with respect to a Clinical Study that was conducted or co-conducted by Ionis, Ionis shall so notify Biogen and shall provide Biogen with a draft thereof at least two Business Days prior to the
                            proposed publication thereof. Biogen may review and provide comments to Ionis and the Parties shall discuss in good faith any such comments and seek to mutually agree on a final version of such proposed public announcement,
                            press release or other public disclosure. Notwithstanding the foregoing, Biogen shall, pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.6, </u></font>retain final decision-making
                            authority over&#160; (i) whether such proposed public announcement, press release or other public disclosure shall be issued or made and (ii) the content thereof, and in no event shall Ionis issue any such public announcement, press
                            release or other public disclosure under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.6</u></font> except in the final version approved by Biogen.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3b9d960f269b4ae7ba1a7085e2d88be4">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Resolution of Disagreements Regarding Public Announcements</u></font>. If the
                            Parties cannot mutually agree on the need for or content of any press release, presentation or other public disclosure under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.5</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.6</u></font> that is intended to be jointly issued, then either Party may promptly refer for resolution to a &#8220;C&#8221; level executive of each Party (e.g., a
                            Party&#8217;s Chief Operating Officer, Chief Executive Officer or Chief Business Officer) or to one of the Party&#8217;s CSC members. During the at least two Business Day advance review period described in <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 11.4.5</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.6</u></font> (as applicable), such &#8220;C&#8221; level executives or CSC members will meet
                            in person at a mutually acceptable time and location or by means of telephone or video conference to discuss in good faith and attempt to resolve such dispute.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">135</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z332671a01ae6429389fd25ab921cc693">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.8.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Scientific or Clinical Presentations for Collaboration Products</u></font>.
                            Regarding any proposed scientific publications or public presentations related to summaries of results from any Clinical Studies generated by Ionis or Biogen for a Collaboration Product, the Parties acknowledge that scientific
                            lead time is a key element of the value of the Collaboration Products under this Agreement and further agree to use Commercially Reasonable Efforts to control public scientific disclosures of the results of the Development
                            activities under this Agreement to prevent any potential 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, whether they are to be presented orally or in written form, at least [***] 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 in order to
                            avoid the unauthorized disclosure of a Party&#8217;s Confidential Information and to preserve the patentability of inventions arising from the Collaboration Programs. If, during such [***] 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 at any time during such [***] day
                            period, the other Party informs such Party that its proposed publication discloses inventions made by either Party in the course of the Development under this Agreement that have not yet been protected through the filing of a
                            patent application, or the public disclosure of such proposed publication could be expected to 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 (a) delay such proposed publication for up to [***] days from the date the other Party informed such Party of its objection to the proposed publication, to permit the timely preparation and first filing of patent
                            application(s) on the information involved or (b) remove the identified disclosures prior to publication. With respect to each Clinical Study, (i) if such Clinical Study is Initiated prior to the date Biogen has been granted a
                            license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font> (as applicable) with
                            respect to the applicable Product, Ionis shall determine authorship or attribution with respect to any proposed publications regarding the results of such Clinical Study and (ii) if such Clinical Study is Initiated after the
                            date Biogen has been granted a license under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(a)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.1(b)</u></font>
                            (as applicable) with respect to the applicable Product, Biogen shall determine authorship or attribution with respect to any proposed publications regarding the results of such Clinical Study, in each case ((i) and (ii)), by
                            interpreting and applying the authorship and attribution principles of the International Committee of Medical Journal Editors&#8217; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Recommendations
                              for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals</font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that (A) in each case, the
                            Party that has the right to determine attribution or authorship in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.7</u></font> shall consider in good faith any reasonable
                            comments timely made by the other Party with respect thereto, (B) any determination of authorship or attribution under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.7</u></font> shall be in
                            compliance with the requirements of the applicable journal of the proposed publication and (C) the Party that does not have the right to determine attribution or authorship in accordance with this <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 11.4.7</u></font> for any such proposed publication will have the right to have at least one author listed in such publication if such Party conducted or co-conducted such Clinical
                            Study.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb1462351ca924661b8c17145b94c0019">

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                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.9.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>SEC Filings</u></font>. 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc9a63cc7468e4969af8f02233c023885">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.10.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Subsequent Disclosure</u></font>. Notwithstanding the foregoing, to the extent
                            information regarding this Agreement or the 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5a084aa8c5134b3ba7ed068894c694d6">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">11.4.11.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Acknowledgment</u></font>. Each Party will acknowledge in any press release,
                            public presentation or publication regarding the Collaboration Programs or a Product, the other Party&#8217;s role in discovering and developing the Product or Discontinued Collaboration Product, as applicable, that the Product is
                            under license from Ionis and otherwise acknowledge the contributions from the other Party, and each Party&#8217;s stock ticker symbol (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>e.g.</u></font>, Nasdaq: IONS,
                            BIIB).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zffd94ee032a84d64aadd7f2591682c28">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen understands and acknowledges the importance to Ionis of continuing to be associated with the drugs it discovers under the Collaboration Programs. As such,
                            Biogen agrees that it will use reasonable efforts to prominently acknowledge Ionis&#8217; role in the discovery of a Product in any scientific, medical and other Product-related communications to the extent such communications address
                            the research, discovery or commercialization of a Product, by prominently including the words &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Discovered by Ionis</font>&#8221; or equivalent language
                            (collectively, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Attribution Language</font>&#8221;) in any such communications; <font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-style: italic;">provided</font>, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">however</font>, that Biogen shall have no obligation to include the
                            Ionis Attribution Language in any of the following: (i) communications or materials where such inclusion would be prohibited by Applicable Laws or applicable Third Party institutional, corporate or other policies; (ii)
                            communications that Biogen does not control, such as publications with non-Biogen lead authors; (iii) materials primarily focused on or directed to patients, or other materials where Biogen branding is not prominently featured;
                            or (iv) abstracts or other communications with a word limitation, if Biogen reasonably determines that such word limitation would preclude the inclusion of the Ionis Attribution Language, <font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-style: italic;">provided that</font>, in each case<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#160;</font>Biogen will use reasonable efforts to have the
                            Ionis Attribution Language included in any such communication, consistent with the efforts that Biogen uses to have statements regarding its own contributions to the Product included in such communication.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis may include the Products (and identify Biogen as its partner for the Product) in Ionis&#8217; drug pipeline.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE 12.</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">MISCELLANEOUS</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2a6a7f7d501c4c54909be2fb72d1d7ff">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Dispute Resolution</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb8e63b5a773d43a1b3c82ef87e22dbdb">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.1.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Escalation</u></font>. In the event of any Dispute (other than a Setoff
                            Dispute, which Setoff Dispute will be resolved pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1.3</u></font>, or dispute regarding the construction, validity or enforcement of either
                            Party&#8217;s Patent Rights, which disputes will be resolved pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.2</u></font>), either Party may, within [***] days after either Party notifies the
                            other Party that the Dispute has not been resolved (<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, that</font> such notice cannot be given less than [***] days after the Dispute has
                            arisen), make a written request that the Dispute be referred for resolution to the Executive Vice President, Business Development of Biogen and the Chief Operating Officer of Ionis (the &#8220;<font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Executives</font>&#8221;). Within [***] days of either Party&#8217;s written request that the Dispute be referred to the Executives, 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 a Dispute. Each Party may elect to have such Party&#8217;s CSC representatives participate in such meeting, if
                            desired, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that it provides the other Party with reasonable advance notice of such intent so as to enable the other Party to have
                            its CSC representatives also participate in such meeting, if desired. If the Executives fail to resolve the Dispute within such [***] day period, then the Dispute will be referred to mediation under <font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u>Section 12.1.2</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7cced657169a438d987dff94fc45497e">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.1.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Mediation</u></font>. If a Dispute subject to <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 12.1.1</u></font> cannot be resolved pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1.1</u></font>, or if neither Party timely makes the
                            written request that the Dispute be referred to the Executives, the Parties will resolve any such Dispute in accordance with the dispute resolution procedures set forth in <font style="font-size: 10pt; font-family: 'Times New
                              Roman'; font-variant: small-caps;"><u>Schedule 12.1.2</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z597a9a878d2242768cc36c9f8efcbefa">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.1.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Setoff Disputes</u></font>. Setoff Disputes will be resolved in accordance with
                            <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.5(b)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 10.4.5(b)</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">138</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z061f671e96e44cf3b17452d8961f4f25">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.1.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Expert Resolution</u></font><font style="font-size: 10pt; font-family: 'Times
                              New Roman'; font-weight: bold;">.</font>&#160;In the event that a matter is referred for expert resolution under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1.4</u></font> pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(d)</u></font> or under <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>, the matter
                            will be resolved by a panel of three (3) industry experts experienced in the issues comprising such dispute.&#160; One expert will be chosen by Ionis, one expert will be chosen by Biogen and the third expert will be chosen by mutual
                            agreement of the experts chosen by Ionis and Biogen.&#160; The place of such expert resolution will be in Chicago, Illinois. Within [***] days after the selection of the third expert (which will occur not later than [***] days after
                            a Party notifies the other Party that it elects to have a dispute resolved pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1.4</u></font>), the Parties will each simultaneously
                            submit to the expert panel and one another a written statement of their respective positions on the relevant dispute.&#160; Each Party will have [***] days from receipt of the other Party&#8217;s submission to submit a written response
                            thereto, which will include any scientific and technical information in support thereof.&#160; The expert panel will conduct at least one hearing at which each Party will have the opportunity to advocate its position before the other
                            Party and the expert panel.&#160; The expert panel will have the right to further meet with both Parties together, as necessary to make a determination.&#160; There will be no <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-style: italic;">ex parte</font> communications between an individual Party and either the expert panel or one or more experts.&#160; All documents submitted will be in the English language.&#160; Further, the expert panel will have
                            the right to request information and materials and to require and facilitate discovery as it will determine is appropriate in the circumstances, taking into account the needs of the Parties and the desirability of making
                            discovery expeditious and cost-effective determinations.&#160; No later than 90 days after the designation of the third expert or as otherwise agreed by the Parties, the expert panel will make a determination.&#160; The expert panel will
                            provide the Parties with a written statement setting forth the basis of the determination in connection therewith.&#160; The decision of the expert panel will be final, binding and conclusive, absent manifest error.&#160; Each Party will
                            bear its attorneys&#8217; fees, costs and disbursements (including, for example, expert witness fees and expenses, photocopy charges, travel expenses, etc.) and the Parties will share equally (50/50) the fees and costs of the expert
                            panel.&#160; Judgment upon any award rendered pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1.4</u></font> may be entered by any court having jurisdiction over the Parties&#8217; assets.&#160;
                            Except to the extent necessary to confirm or enforce an award or as may be required by law, neither Party nor any of the experts may disclose the existence, content or results of any proceeding under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1.4</u></font> without the prior written consent of both Parties.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze1b39b84b1594421b296b2bff618e879">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Governing Law; Jurisdiction; Venue; Service of Process</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze7bb8f163be0468486a3df02905d80ff">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.2.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">This Agreement and any Dispute will be governed by and construed and enforced in accordance with the laws of the State of Delaware, U.S.A., without reference to
                            conflicts of laws principles.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">139</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdbab734bb4c84c6e9cb995f8ce366d75">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.2.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Subject to the provisions of <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font>, each Party by its execution hereof, (a)
                            hereby irrevocably submits to the exclusive jurisdiction of the United States District Court for the District of Delaware (or, if but only if such court lacks, or will not exercise, subject matter jurisdiction over the entirety
                            of a Dispute, the Court of Chancery of&#160; the State of Delaware, or, if but only if such court lacks, or will not exercise, subject matter jurisdiction over the entirety of a Dispute, the Superior Court of the State of Delaware,
                            with respect to the Dispute) for the purpose of any Dispute arising between the Parties in connection with this Agreement (each, an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style:
                              italic;">Action</font>&#8221;) and (b) hereby waives to the extent not prohibited by Applicable Law, and agrees not to assert, by way of motion, as a defense or otherwise, in any such Action, any claim that it is not subject
                            personally to the jurisdiction of the above-named courts, that venue in the above-named courts&#160; is improper, that its property is exempt or immune from attachment or execution, that any such Action brought in the above-named
                            courts should be dismissed on grounds of forum non conveniens, should be transferred or removed to any court other than the above-named courts, or should be stayed by reason of the pendency of some other proceeding in any other
                            court other than the above-named courts, or that this Agreement or the subject matter hereof may not be enforced in or by such courts and (c) hereby agrees not to commence any such Action other than before the above-named
                            courts.&#160; Notwithstanding the previous sentence, a Party may commence any Action in a court other than the above-named court solely for the purpose of enforcing an order or judgment issued by the above-named court.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb4232df5f8e340da80f9c3fc75b1a46e">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.2.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Each Party hereby agrees that service of process: (a) made in any manner permitted by Delaware law, or (b) made by overnight express courier service (signature
                            required), prepaid, at its address specified pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>12.8</u></font>,
                            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.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb301e5c35ff14333bb2c776c3ccfbf72">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Remedies</u></font>. 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 will be entitled to recover any Losses relating to any matter arising under one provision of this Agreement to the extent that such Party has already recovered Losses with respect to
                            such matter pursuant to other provisions of this Agreement (including recoveries under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.1</u></font> or <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 9.2</u></font>, and the offsets under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(c)</u></font>).&#160; Except for the offsets and credits explicitly set forth in
                            <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.3</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.15</u></font>, <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section 6.13.3(b)</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.3(d)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section







                                10.4.5(b)</u></font>, 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>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">140</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0031dc8256484b388c15943876327681">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Assignment and Successors</u></font>. Neither this Agreement nor any obligation
                            of a Party hereunder may be assigned by either Party without the consent of the other, which will not be unreasonably withheld, delayed or conditioned, except that each Party may assign this Agreement and the rights, obligations
                            and interests of such Party, in whole or in part, without the other Party&#8217;s consent, to any of its Affiliates, to any purchaser of all or substantially all of its assets 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>,
                            if Biogen transfers or assigns this Agreement to [***] described in this Agreement, then Biogen (or such Affiliate), will [***] due Ionis under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 6</u></font>
                            for the [***] assignment. In addition, Ionis may assign or transfer its rights to receive payments under this Agreement (but no liabilities), without Biogen&#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 <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.4</u></font> will be null and void.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">To the extent Ionis utilizes a [***] in any year, Ionis will [***] to Biogen [***]. To assist Biogen in determining when a
                refund is due from Ionis pursuant to the foregoing sentence, beginning with the first Annual tax return for the year in which Biogen [***] payment under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.4</u></font>,
                and each year thereafter (including, for clarity, all years in which Ionis utilizes a [***], Ionis will provide Biogen with Ionis&#8217; Annual tax returns (federal and state) and, in years in which Ionis utilizes [***], supporting documentation
                for such [***]. Notwithstanding the foregoing, if the [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z09aa02adb2634ff083c99810749d0218">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Change of Control</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z728a87c05aec41caba846ef74279cc50">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.5.1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Research Activities</u></font><font style="font-size: 10pt; font-family: 'Times
                              New Roman'; font-weight: bold;">. </font>If, at any time during the Research Term, a Change of Control of Ionis occurs, then at any time prior to the [***] anniversary of the closing of such Change of Control, upon written
                            notice to Ionis, Biogen may either:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc4ab0e28fd0e423399855d9a6e82c9f1">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Extend the Research Term until such time as Ionis has completed target validating activities that are Ionis Activities under the Neurological Disease Research Plan
                            for a total of [***] High Interest Targets;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">141</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf8c854d7bf534d3d89fd474cd781c387">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Terminate the Research Term, in which case: (i) Ionis will complete all ongoing target validation work that are Ionis Activities under the Neurological Disease
                            Research Plan and advance each such target to Target Sanction (but for clarity, no target validation work will be initiated for any new target under the Neurological Disease Research Plan); (ii) Ionis will complete all ongoing
                            Ionis Activities under the Core Research Plan (but for clarity, no new work will be initiated under the Core Research Plan); (iii) for each Collaboration Target that is not an ALS Target that reaches Target Sanction or each ALS
                            Target designated a Collaboration Target, an ASO Development Candidate Identification Plan will be prepared and Ionis will carry out its obligations under such plan, all in accordance with <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section 1.10.1</u></font>; (iv) Ionis will continue to perform its obligations under each ongoing ASO Development Candidate Identification Plan until the end of the applicable ASO
                            Development Candidate Identification Term and under each ongoing Initial Development Plan until completion of all Ionis Activities thereunder; (v) for each Collaboration Program for which a Development Candidate is identified as
                            provided herein, Biogen may, upon written notice to Ionis, such notice to be delivered within [***] days after designating a Development Candidate for the applicable Collaboration Program, elect to either (A) exercise the
                            applicable Option by notifying Ionis in writing of Biogen&#8217;s election to license the Collaboration Product [***] and will be paid to Ionis within [***] days after Biogen&#8217;s election under clause (A) of this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.5.1(b)</u></font>, and after such exercise, Biogen will not be obligated [***], or (B) establish an Initial Development Plan for such Collaboration Program
                            pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(d)</u></font>, in which case Ionis and Biogen will continue to exercise their rights and perform their respective obligations with
                            respect to the applicable Collaboration Program under the terms of this Agreement; (vi) the Research Term will end upon Ionis&#8217; completion of all Ionis Activities under clauses (i), (ii) and (iii) above; and (vii) within [***]
                            days after the end of the Research Term, Ionis will [***]; or</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z70e4bc01adee44cfa3412b2321ebf487">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Allow such [***] period to lapse without providing any such notice of election under this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                                12.5.1</u></font>, in which case Ionis and Biogen will continue to exercise their rights and perform their respective obligations under the terms of this Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc59a9b30922b4b50916c5acf59166b19">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.5.2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Pre-Existing Competitive Collaboration Programs </u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>of an Acquirer</u></font>. If, at any time during the Agreement Term, a Change of Control of a Party occurs involving a Person that, at the time of
                            the execution of such Change of Control, is (A) developing or commercializing a (1) Competitive Product or (2) Competitive Indication Collaboration Product within the Field (such pre-existing Competitive Collaboration Products
                            and Competitive Indication Products, each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Existing Competitive </font><font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-weight: bold; font-style: italic;">Collaboration Product</font>&#8221;) or (B) is engaged in a (1) Competitive Collaboration Program or (2) Competitive Indication Program (such pre-existing Competitive
                            Collaboration Programs and Competitive Indication Collaboration Programs, each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Existing Competitive Collaboration
                              Program</font>,&#8221; and such Person being hereinafter referred to as a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competing Collaboration Acquirer</font>&#8221;), then in each
                            case ((A) and (B)):</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">142</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za41a36bbc730459e95ff9494a6e8caa1">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">such Party shall promptly provide written notice to the other Party of such Change of Control;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z74a993a420e74561b1837f1b77204c70">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">if such Change of Control involved Ionis, then Biogen may elect that some or all of the Biogen Reduced Participation and Information Obligations will apply to the
                            Collaboration Programs to which the Pre-Existing Competitive Collaboration Product or Pre-Existing Competitive Collaboration Program relate;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8c9ee395b1e04b319a18d3ccadaf07f8">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">such Party shall conduct activities pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u> 12.6</u></font>&#160;to separate its Development activities under this Agreement from its development activities relating to any Pre-Existing Collaboration Competitive Product(s) and
                            Pre-Existing Competitive Collaboration Program(s);</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z50a6c2f44bd946cbadbfca92c5c07bff">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">the research, development, manufacture or commercialization of any Pre-Existing Competitive Collaboration Product(s) by a Competing Collaboration Acquirer will not
                            be a violation of such Party&#8217;s exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 2.1.1</u></font>&#160;and







                            <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.3(a)</u></font>&#160;will not apply to any such Pre-Existing Competitive
                            Collaboration Product or Pre-Existing Competitive Collaboration Program; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that the conditions of<font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u> Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.2(a)</u></font>&#160;and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.2(c)</u></font>&#160;are satisfied.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zae56de1f76594cb887b2be8268d0824c">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.5.3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Acquired Competitive Programs; Acquired Associated Programs</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze3ef04dc90784125aa2a466bcb8b85ef">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If, at any time during the Agreement Term, either Party acquires a Third Party or a portion of the business of a Third Party (whether by merger, stock purchase or
                            purchase of assets) that is, prior to such acquisition, engaged in discovering, researching, developing or commercializing a Competitive Collaboration Product within the Field or is engaged in a Competitive Collaboration
                            Program, in each case that would violate the provisions of&#160;<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 2</u></font>&#160;if conducted by such Party (such acquired Competitive Collaboration Product an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Acquired Competitive Product</font>&#8221; and such acquired Competitive Collaboration Program an &#8220;<font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Acquired Competitive Program</font>&#8221;), then the limited continuation of the research, development, manufacture or commercialization of the Acquired
                            Competitive Product(s) or Acquired Competitive Programs by the acquiring Party as permitted in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u> 12.5.3(a)</u></font>&#160;in a manner that would have been in the ordinary course of business of such Third Party will not be a violation of such acquiring Party&#8217;s exclusivity covenants under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 2.1.1</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-style: italic;">provided that</font>, following the closing of such acquisition, the conditions set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Sections</u></font><font style="font-size:
                              10pt; font-family: 'Times New Roman';"><u> 12.5.3(a)(i)</u></font>&#160;through <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>12.5.3(a)(iv)</u></font>&#160;are met:</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">143</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z49f7b29d374c49f2bca780234163161d">

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                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Such acquiring Party shall promptly provide written notice to the other Party of such acquisition;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8a1f628b7ec34d9cab2afac72b836951">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(ii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Such acquiring Party shall use reasonable efforts to divest all such Acquired Competitive Products and Acquired Competitive Programs promptly following the closing
                            of such acquisition, and in any event such Party shall complete such divestment within [***] after the closing of such acquisition (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                              font-style: italic;">Collaboration Divestiture Period</font>&#8221;); provided that such Collaboration Divestiture Period shall be extended, and such Party shall not be in breach of this <font style="font-size: 10pt; font-family:
                              'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.3(a)</u></font>&#160;if, at the expiration thereof (and any extensions thereto), such Party provides competent
                            evidence of reasonable ongoing efforts to divest such Acquired Competitive Products and Acquired Competitive Programs; provided, further, that such Party shall cease all development and commercialization activities with respect
                            to all such Acquired Competitive Products and Acquired Competitive Programs if such Party has not completed such divestiture within [***] after the closing of such acquisition (it being understood that such Party may thereafter
                            continue its efforts to divest such asset);</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z89678e98b29944b0aca9460bf095014b">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iii)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">During such divestiture period, the acquiring Party shall comply with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>12.6</u></font> to separate its Development activities under this Agreement from its development activities relating to any Acquired Competitive Product or Acquired
                            Competitive Program; and</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z263153b765f14c3b9529ac8446d90c9f">

                    <tr>
                      <td style="width: 117pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(iv)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Neither Party nor its Affiliates may acquire a Competitive Product or a Competitive Program on a standalone basis.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zef08992d296d45c89cff7667fcd28c2d">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Ionis is the acquiring Party of an Acquired Competitive Product or Acquired Competitive Program, then during the Collaboration Divestiture Period until Ionis
                            [***], Biogen may elect that [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">144</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfa7370be02bb41efb5bf666dac29f1a0">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">In addition, without limiting <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times
                              New Roman';"><u> 12.5.3(a)(iv)</u></font>, if at any time during the Agreement Term, (i) Ionis acquires a Third Party or a portion of the business of a Third Party (whether by merger, stock purchase or purchase of assets) that
                            is, prior to such acquisition, engaged (A) in [***] (an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Associated Product</font>&#8221;) or any Competitive Indication
                            Collaboration Product, or (B) is engaged in [***] (an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Associated Program</font>&#8221;) or a Competitive Indication Collaboration
                            Program, (ii) Ionis or an Ionis Affiliate [***] or (iii) Ionis or an Ionis Affiliate [***]<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">&#160;</font>then, in each case ((i)
                            through (iii)) with respect to any Collaboration Program directed to the Collaboration Target to which the Associated Product, Associated Program, Competitive Collaboration Product or Competitive Collaboration Program is
                            directed and with respect to any Collaboration Program intended for the same indication as the Competitive Indication Collaboration Product or the Competitive Indication Collaboration Program, Biogen may elect that [***] and
                            Ionis shall comply with the same procedures as under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>12.6</u></font>&#160;to
                            separate its Development activities under this Agreement from its development activities relating to any such Associated Product, Associated Program, Competitive Collaboration Product, Competitive Collaboration Program,
                            Competitive Indication Collaboration Product or Competitive Indication Collaboration Program.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z73ba8ee70d4f474dadf61da682460fa5">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.5.4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Biogen Alternate Modality Programs</u></font><font style="font-size: 10pt;
                              font-family: 'Times New Roman'; font-weight: bold;">. </font>On a Biogen Alternate Modality Product-by-Biogen Alternate Modality Product basis, if, at any time during the Agreement Term, a Change of Control occurs involving
                            Ionis and a Person that, at the time of the closing of such Change of Control, is developing in human clinical trials or commercializing a Directly Competitive Biogen Alternate Modality Product within the Field or is engaged in
                            a Directly Competitive Biogen Alternate Modality Program or, at any time during the Agreement Term after such closing of the Change of Control, develops or acquires a Directly Competitive Biogen Alternate Modality Product or
                            begins a Directly Competitive Biogen Alternate Modality Program (such Person being hereinafter referred to as a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competing
                              Alternate Modality Acquirer</font>&#8221;) and such Competing Alternate Modality Acquirer has not, within [***] of either (i) closing of the Change of Control in the event the Directly Competitive Biogen Alternate Modality Product
                            is being developed in human clinical trials or commercialized, or the Directly Competitive Biogen Alternate Modality Program exists, as of such closing date or (ii) the date of first development or acquisition of such Directly
                            Competitive Biogen Alternate Modality Product or the date on which such Competing Alternate Modality Acquirer begins such Directly Competitive Biogen Alternate Modality Program (the &#8220;<font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-weight: bold; font-style: italic;">Alternate Modality Divestiture Period</font>&#8221;) divested itself of the Directly Competitive Biogen Alternate Modality Product or Directly Competitive Biogen Alternate
                            Modality Program, terminated development and commercialization of such Directly Competitive Biogen Alternate Modality Product or such Biogen Alternate Modality Program or assigned this Agreement pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.4</u></font> to a Third Party that is not itself developing or commercializing a Directly Competitive Collaboration Product or engaged in a Directly
                            Competitive Biogen Alternate Modality Program, then (i) Ionis will provide written notice to Biogen of the closing of such Change of Control or Alternate Modality Divestiture Period, as applicable, and (ii) [***].&#160; For clarity,
                            Biogen&#8217;s rights as set forth in this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.5.4</u></font> shall be Biogen&#8217;s exclusive remedies for the failure of a Competing Alternate Modality Acquirer to
                            divest or terminate development and commercialization of a Directly Competitive Biogen Alternate Modality Product or Directly Competitive Collaboration Program or assigned this Agreement to an applicable Third Party, in each
                            case, during the Alternate Modality Divestiture Period in accordance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.5.4</u></font>.</font></div>
                      </td>
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                </table>
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            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">145</font></div>
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              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z17727c71fb3047d1832b8970e7154d34">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Protective Provisions</u></font><font style="font-size: 10pt; font-family:
                              'Times New Roman'; font-weight: bold;">. </font> At any time while (a) the Party involved in a Change of Control with a Competing Collaboration Acquirer or Competing Alternate Modality Acquirer, (b) the Party with an Acquired
                            Competitive Product or Acquired Competitive Program or (c) Ionis (in cases where Ionis otherwise has an Associated Product, Associated Program, Competitive Product, Competitive Program, Competitive Indication Product or
                            Competitive Indication Program) is conducting Development activities under this Agreement, then, in each case ((a) through (c)) such Party (as applicable under clause (a), (b) or (c)) must separate such Development activities
                            from its or its Affiliates&#8217; other development activities relating to any such Competitive Collaboration Product, Competitive Collaboration Program, Directly Competitive Biogen Alternate Modality Product or Directly Competitive
                            Biogen Alternate Modality Program and, in the case of Ionis, from any such Associated Product, Associated Program, Competitive Indication Product or Competitive Indication Program, as applicable (such other development
                            activities, &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competing Development Activities</font>&#8221;). To that end, and subject to the licenses granted to each Party (as
                            applicable) under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3</u></font>&#160;or <font style="font-size: 10pt;
                              font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.4</u></font>, any such Party will, and (if applicable) will cause the Competing Collaboration Acquirer
                            or Competing Alternate Modality Acquirer to, (i) establish separate teams to conduct Development activities under this Agreement and such Competing Development Activities, (ii) prevent any Confidential Information relating to
                            the Development, Manufacture or Commercialization of any applicable Product (including Know-How) from being disclosed to, or used by, individuals performing such Competing Development Activities and (iii) not use or reference in
                            the development, manufacture or commercialization of the Competitive Collaboration Product or Directly Competitive Biogen Alternate Modality Product, any Know-How that is Confidential Information or conduct any activities
                            Covered by any Patent Rights, in each case Controlled by the Party involved in the Change of Control or the acquisition or its Affiliates prior to the effective date of the Change of Control or the acquisition.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf9b82753e0644146b0cd438d4ef8d963">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.7.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Force Majeure</u></font>. 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.&#160; 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 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>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">146</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zca5901f73b8e4dbb8ec0e2c4ea22bc17">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.8.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Notices</u></font>. Any notice or request required or permitted to be given
                            under or in connection with this Agreement will be deemed to have been sufficiently given if in writing and personally delivered or sent by certified mail (return receipt requested), electronic mail 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> <br>
                </div>
              </div>
            </div>
            <table cellspacing="0" cellpadding="0" border="0" style="border-collapse: collapse; width: 90%; font-family: &quot;Times New Roman&quot;; font-size: 10pt; margin-left: 36pt;" id="zca642017ee89442f95b3aab424c98f9a">

                <tr>
                  <td style="width: 25%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">If to Ionis, addressed to:</font></font></div>
                  </td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Ionis Pharmaceuticals, Inc.</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">2855 Gazelle Court</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Carlsbad, CA&#160; 92010</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Attention:&#160; Chief Operating Officer</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">E-mail: [***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">&#160;</td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">with a copy to:</font></font></div>
                  </td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Ionis Pharmaceuticals, Inc.</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">2855 Gazelle Court</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Carlsbad, CA&#160; 92010</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Attention:&#160; General Counsel</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">E-mail: [***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">&#160;</td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">If to Biogen, addressed to:</font></font></div>
                  </td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen MA Inc.</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">225 Binney Street</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Cambridge, MA 02142</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Attention: Chief Legal Officer</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">E-mail: [***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">&#160;</td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">with a copy to:</font></font></div>
                  </td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Ropes &amp; Gray LLP</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Prudential Tower</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">800 Boylston Street</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Boston, MA 02199-3600</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Attention: </font>Mark Bellomy<font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">, Esq.</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 25%; vertical-align: top;">&#160;</td>
                  <td style="width: 65%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Email: mark.bellomy@ropesgray.com</font></div>
                  </td>
                </tr>

            </table>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">or to such other address for such Party as it will have specified by like notice to the other Party; <font style="font-size:
                  10pt; font-family: 'Times New Roman'; font-style: italic;">provided </font>that notices of a change of address will be effective only upon receipt thereof.&#160; If delivered personally or by electronic mail 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.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">147</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z67a362f5f1674f34b243e0c024441902">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.9.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Export Clause</u></font>. Each Party acknowledges that the Laws of the United
                            States restrict the export and re-export of commodities and technical data of United States origin.&#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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7f11950c27054b38ba52ed6b18c15e5d">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.10.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Waiver</u></font>. Neither Party may waive or release any of its rights or
                            interest 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z612468bd116b43b8bdef574099899930">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.11.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Severability</u></font>. If any provision hereof should be held invalid,
                            illegal or unenforceable in any jurisdiction, then the Parties will negotiate in good faith a valid, legal and enforceable substitute provision that most nearly reflects the original intent of the Parties and all other
                            provisions hereof will remain in full force and effect in such jurisdiction and will be liberally construed in order to carry out the intentions of the Parties 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zd9b7623415584579bc39eebbca41030c">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.12.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Entire Agreement</u></font>. This Agreement (together with the Schedules and
                            Appendices hereto, including the ALS Letter Agreement), amends and restates the First Amended and Restated Agreement, is a comprehensive and integrated statement of the agreement between the Parties with respect to the subject
                            matter hereof and fully supersedes the the First Amended and Restated Agreement for the period commencing on the Second Amendment Date and continuing thereafter. Without limiting the foregoing, this Agreement supersedes that
                            certain side letter between the Parties, dated as of October 9, 2015, relating to drug substance process development and manufacturing, solely to the extent such side letter relates to Collaboration Programs under this
                            Agreement. For clarity, such side letter shall remain in full force and effect with respect to the Ionis/Biogen Additional Agreements. For the avoidance of doubt, this Agreement in no way supersedes, modifies or otherwise
                            affects any of the Ionis/Biogen Additional Agreements, which will remain in full force and effect in accordance with each of their respective terms. There are no covenants, promises, agreements, warranties, representations,
                            conditions or understandings, either oral or written, between the Parties with respect to the subject matter hereof other than as set forth herein. No subsequent alteration, amendment, change or addition to this Agreement will
                            be binding upon the Parties hereto unless reduced to writing and signed by the respective authorized officers of the Parties.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">148</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z955549a19e204081bc7f8b0b24cd5105">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.13.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Independent Contractors</u></font>. Nothing herein will be construed to create
                            any relationship of employer and employee, agent and principal, partnership or joint venture between the Parties. Each Party is an independent contractor. 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfc42f97666ea4d748df1f0aa92773fe0">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.14.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Interpretation</u></font>. 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;shall&#8221; and &#8220;will&#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, (h) unless otherwise specified, &#8220;$&#8221; is in reference to United States dollars and (i) 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z602db193cc1247f3b3ba793b9b3974b5">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.15.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Books and Records</u></font>. Any books and records to be maintained under this
                            Agreement by a Party or its Affiliates or Sublicensees will be maintained in accordance with GAAP (or any successor standard), consistently applied.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z26bb44e121644a9d94b319742e526e37">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.16.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Further Actions</u></font>. Each Party will execute, acknowledge and deliver
                            such further instruments, and do all such other acts, as may be necessary or appropriate in order to carry out the expressly stated purposes and the clear intent of this Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc79b817694ef47679dd9e52185f89cf3">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.17.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Construction of Agreement</u></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>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">149</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z23b25d76b27c4927a36bdf7f551c8295">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.18.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Supremacy</u></font>. 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z63f165e2133d4f2aa4c694c52d23ee83">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.19.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Counterparts</u></font>. This Agreement may be signed in counterparts, each of
                            which will be deemed an original, notwithstanding variations in format or file designation that 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>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc2645d89970b4c33866f62e57f449d16">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">12.20.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Compliance with Laws</u></font>. Each Party will, and will ensure that its
                            Affiliates and Sublicensees will, comply with all relevant Laws and regulations and good laboratory and clinical practices and cGMP in exercising its rights and fulfilling its obligations under this Agreement.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">[SIGNATURE PAGE FOLLOWS]</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">* - * - * - *</font></font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">150</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">IN WITNESS WHEREOF</font>,
                the Parties have caused this Agreement to be executed by their representatives thereunto duly authorized as of the Second Amendment Date.</font></div>
            <div><br>
            </div>
            <table cellspacing="0" cellpadding="1" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse;" id="z12ae4ee1532c47fd8b662f27a62646c4">

                <tr>
                  <td colspan="3" style="vertical-align: top;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">BIOGEN MA INC.</font></div>
                  </td>
                </tr>
                <tr>
                  <td colspan="3" style="vertical-align: top;">&#160;</td>
                </tr>
                <tr>
                  <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">By:</font></font></div>
                  </td>
                  <td style="width: 30%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman';">/s/ Michael Ehlers</font></font></div>
                  </td>
                  <td style="width: 67%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
                </tr>
                <tr>
                  <td colspan="3" style="vertical-align: top;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Name: Michael Ehlers</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td colspan="3" style="vertical-align: top;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Title: EVP, Research &amp; Development</font></font></div>
                  </td>
                </tr>

            </table>
            <div>
              <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps; font-weight: bold;"> <br>
              </div>
              <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps; font-weight: bold;">Signature Page to Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration,
                Option and License Agreement</div>
              <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps; font-weight: bold;"> <br>
              </div>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">IN WITNESS WHEREOF</font>, the Parties have
                caused this Agreement to be executed by their representatives thereunto duly authorized as of the Amendment Date.</font></div>
            <div><br>
            </div>
            <table cellspacing="0" cellpadding="1" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse;" id="zdac4f9bc6eaf41cfaa93a874fb9a840f">

                <tr>
                  <td colspan="3" rowspan="1" style="vertical-align: top;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</font></div>
                  </td>
                </tr>
                <tr>
                  <td colspan="3" rowspan="1" style="vertical-align: top;">&#160;</td>
                </tr>
                <tr>
                  <td style="width: 3%; vertical-align: top; padding-bottom: 2px;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">By:</font></font></div>
                  </td>
                  <td style="width: 30%; vertical-align: top; border-bottom: 2px solid black;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">/s/ Brett P. Monia</font></font></div>
                  </td>
                  <td style="width: 67%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
                </tr>

            </table>
            <table cellspacing="0" cellpadding="0" border="0" id="zd0d3508b18214b559d828944b86e477a" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse;">

                <tr>
                  <td style="width: 4%; vertical-align: top; padding-bottom: 2px;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Name:</font></font></div>
                  </td>
                  <td style="width: 30%; vertical-align: top; border-bottom: 2px solid black;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">&#160;Brett P. Monia</font></font></div>
                  </td>
                  <td style="width: 66%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
                </tr>

            </table>
            <table cellspacing="0" cellpadding="0" border="0" id="z13893c292180448694ec5878426b74b2" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse;">

                <tr>
                  <td style="width: 4%; vertical-align: top; padding-bottom: 2px;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Title:</font></font></div>
                  </td>
                  <td style="width: 45%; vertical-align: top; border-bottom: 2px solid black;">
                    <div style="text-align: justify;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Chief Operating Officer/SVP Translational Medicine</font></font></div>
                  </td>
                  <td style="width: 51%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
                </tr>

            </table>
            <div>
              <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps; font-weight: bold;"> <br>
              </div>
              <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt; font-variant: small-caps; font-weight: bold;">Signature Page to Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration,
                Option and License Agreement</div>
              <div><br>
              </div>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>List of Appendices and Schedules</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 1</u></font> &#8211; Definitions</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 2</u></font> &#8211; Development Candidate Checklist</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font> &#8211; Multi-Indication Target Process</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 4</u></font> &#8211; Form of Side Letter</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.1.4</u></font> &#8211; Biogen Conducted Non-ALS
                Targets</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font> &#8211; Terms and Conditions for
                Provision of Research ASOs to Biogen</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 1.6.1</u></font> &#8211; ALS Letter Agreement</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>1.10.2(c)</u></font> &#8211; Ionis&#8217; Standard IND-Enabling Toxicology Studies</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>1.10.2(d)</u></font> &#8211; Initial Development Plan Requirements</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>1.10.2(d)(v)</u></font> &#8211; Study Synopsis Requirements</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>1.10.2(e)</u></font> &#8211; Apportionment of Certain Milestone Payments and Biogen-Approved Costs</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.10.6</u></font> &#8211; Ionis API Supply for ALS
                Collaboration Programs and Biogen Conducted Non-ALS Collaboration Programs</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.18.1</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-variant: small-caps;"> &#8211; </font>Collaboration Steering Committee Governance</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.18.2</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-variant: small-caps;"> &#8211; </font>Neurology JRC Governance</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.18.3</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-variant: small-caps;"> &#8211; </font>Neurology JDC Governance</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.18.6</u></font> &#8211; Alliance Management
                Activities</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>4.3.1(a)</u></font> &#8211; Drug Substance Process and Formulation Development Activities</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>4.8.2(c)</u></font> &#8211; Ionis&#8217; Fully Absorbed Cost of Goods Methodology</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 5.1.4</u></font> &#8211; Biogen&#8217;s Development and Commercialization Activities</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 5.1.6</u></font> &#8211; Integrated Development Plan
                Content</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>6.10.2(e)</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"> &#8211; </font>Royalty Calculation Examples</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>6.10.2(f)</u></font> &#8211; Allocation of Net Sales</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 6.13.1</u></font> &#8211; Certain Ionis In-License Agreements</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 8.2.4(a)</u></font> &#8211; Ionis Core Technology Patents</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 8.2.4(b)</u></font> &#8211; Ionis Manufacturing and Analytical Patents</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 8.2.4(c)</u></font> &#8211; Ionis Product-Specific Patents</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 8.2.8</u></font> &#8211; Prior Agreements</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 10.4.5(b)</u></font> &#8211; Advisory Panel Regarding Setoff Disputes</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 10.4.6</u></font> &#8211; Transition Services</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 12.1.2</u></font> &#8211; Mediation</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 12.5</u></font> &#8211; Applicable License Fee Payments in Change of Control for Collaboration Products, and [***]</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">153</font></div>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Appendix 1</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">DEFINITIONS</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For purposes of this Agreement, the following capitalized terms will have the following meanings:</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Accelerated Target</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.4.</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New
                  Roman'; font-style: italic;">filed</font>,&#8221; (b) in the European Union, receipt by Biogen 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-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided </font>that 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, (c) in any Major Market in Europe that is not a European Union country, receipt by Biogen of written notice of acceptance by the applicable
                Regulatory Authority of such MAA for filing in such country, and (d) in Japan, receipt by Biogen of written notice of acceptance of filing of such JNDA from the Koseisho (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">,</font> the Japanese Ministry of Health and Welfare, or any successor agency thereto).</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Acquired Competitive Product</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.3(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Acquired Competitive Program</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.3(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Action</font>&#8221; has the meaning set forth in
                <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.2.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Actual Biogen-Approved Costs</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1(e)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Additional Core IP</font>&#8221; means Third Party
                intellectual property that is necessary to [***]. For clarity, Additional Core IP does not include any Patent Rights claiming (or intellectual property related to) [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Additional Plan Costs</font>&#8221; means [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Advisory Panel</font>&#8221; has the meaning in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 10.4.5(b)</u></font> of this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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, at least 50% of the outstanding voting securities or capital stock (or such lesser percentage which is the maximum allowed to be owned by a foreign corporation in a particular jurisdiction) of
                such other 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. For clarity, Regulus Therapeutics Inc. will not be deemed an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Affiliate</font>&#8221; of Ionis for the purposes of this Agreement under any
                circumstances.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">154</font></div>
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            <font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Agreement</font>&#8221; has the meaning set forth in the Preamble of this Agreement.</font>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Agreement</font>&#160;<font style="font-size:
                  10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Term</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Alliance Manager</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.6</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">ALS&#8221; </font>means the disease amyotrophic
                lateral sclerosis.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">ALS Collaboration Program</font>&#8221; means a
                Collaboration Program focused on an ALS Target.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#8220;</font><font style="font-size: 10pt; font-weight: bold;
                  font-style: italic;">ALS</font><font style="font-weight: bold; font-style: italic;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Deadline</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3.</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#8220;</font><font style="font-size: 10pt; font-weight: bold;
                  font-style: italic;">ALS</font><font style="font-weight: bold; font-style: italic;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Licensing Milestone Event</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.5.</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">ALS Target</font>&#8221; means the initial
                ALS-associated High Interest Targets identified as ALS Targets on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>
                    1.2.3(a)</u></font> on the Effective Date, plus any ALS-associated High Interest Target that is designated as an ALS Target in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2.3(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">ALS Target List</font>&#8221; means the list of
                ALS-associated High Interest Targets identified as ALS Targets on the High Interest Target List.&#160; For clarity, at any given time, if a gene target is not on the ALS Target List at such time, then such gene target is not an ALS Target.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Alternate Modality</font>&#8221; means a
                therapeutic approach for a gene target that is not an Oligonucleotide approach.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Alternate Modality Divestiture Period</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.5.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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).</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">API</font>&#8221; means the bulk active
                pharmaceutical ingredient manufactured in accordance with cGMP for a Collaboration Product.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Applicable Law</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">155</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Approval</font>&#8221; means, with respect to a
                Product in any regulatory jurisdiction, approval from the applicable Regulatory Authority sufficient for the manufacture, distribution, use, marketing and sale of such Product in such jurisdiction in accordance with Applicable Laws. In
                jurisdictions where the applicable Regulatory Authority sets the pricing or reimbursement authorizations necessary for the general marketing and sale of such Product in the marketplace, Approval will not be deemed to have occurred if the
                final approval to market and sell such Product is being withheld because Biogen (or its Affiliate or Sublicensee) and the Regulatory Authority have not yet determined pricing or reimbursement even if all other approvals, licenses,
                registrations or authorizations necessary for marketing, sale or use of such Product in such jurisdiction have been obtained. &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Approval</font>&#8221; does not
                include authorization by a Regulatory Authority to conduct named patient, compassionate use or other similar activities.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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, excluding any double stranded Oligonucleotide compounds that are designed to act through the RNA-induced silencing complex.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">ASO Development Candidate Identification
                  Plan</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">ASO Development Candidate Identification
                  Term</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Associated Product</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.3(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Associated Program</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.5.3(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Audit Report</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.15</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Bankruptcy Code</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.7(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen</font>&#8221; has the meaning set forth in
                the Preamble of this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Activities</font>&#8221; means, under any
                Neurology Plan, any and all research, pre-clinical and/or clinical activities that Biogen agrees to conduct; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> that Biogen will be deemed to
                have agreed to conduct any activities designated as Biogen Activities under any Neurology Plan it approves.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Alternate Modality Milestone Event</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Alternate Modality Product</font>&#8221;
                means a finished drug product that contains a molecule that is (i) not an Oligonucleotide, (ii) designed to bind, mimic or otherwise affect a protein or RNA that is encoded by a Biogen Alternate Modality Target, and (iii) discovered by
                Biogen or its Affiliates or any Third Party acting on their behalf.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Alternate Modality Program</font>&#8221;
                means a program to discover, Develop, Manufacture and Commercialize a Biogen Alternate Modality Product.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">156</font></div>
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            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Alternate Modality Royalty</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.9.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Alternate Modality Royalty Period</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.9.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Alternate Modality Target</font>&#8221; is
                either (i) a High Interest Target that is designated as a Biogen Alternate Modality Target under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.3,</u></font>&#160;<font style="font-size: 10pt; font-family: 'Times
                  New Roman';"><u>Section 1.4</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8</u></font>, (ii) a Collaboration Target that is changed to a Biogen Alternate Modality Target under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.2</u></font>, or (v) a Collaboration Target that is added as a Biogen Alternate Modality Target under<font style="font-weight: normal;"> <font style="font-size:
                    10pt; font-family: 'Times New Roman';"><u>Section </u></font></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u><font style="font-weight: normal;">3.2.4.2.</font><br>
                  </u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen-Approved Changes</font>&#8221; means any
                changes (including number of subjects, duration of dosing, additional studies, additional endpoints, additional analysis, etc.) to the applicable Neurology Plan for a Product that are requested by either Party after the Parties have set the
                initial Cost Estimates for such Neurology Plan under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>, and (i) required by a Regulatory Authority or (ii) agreed to be paid for by Biogen.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen-Approved Costs</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Conducted Non-ALS Collaboration
                  Program</font>&#8221; means a Collaboration Program focused on a Biogen Conducted Non-ALS Target.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Conducted Non-ALS</font>&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Deadline</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3.</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Conducted Non-ALS Target</font>&#8221;
                means each of the High Interest Targets listed on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.1.4</u></font>, which may be updated by mutual written agreement of the Parties to
                include additional High Interest Targets relating to [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Full Royalty</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Know-How</font>&#8221; means any Know-How
                owned, used, developed by, or licensed to Biogen or its Affiliates, in each case to the extent Controlled by Biogen or its Affiliates on the Effective Date or at any time during the Agreement Term, <font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-style: italic;">but specifically excluding</font> the Biogen Program Know-How.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Manufacturing Program Patents</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8.3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Patents</font>&#8221; means any Patent
                Rights included in the Biogen Technology.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Product-Specific Patents</font>&#8221;
                means all Product-Specific Patents owned, used, developed by, or licensed to Biogen or its Affiliates, in each case, to the extent Controlled by Biogen or its Affiliates on the Effective Date or at any time during the Agreement Term.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Program Know-How</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Program Patents</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Program Technology</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen-Prosecuted Patents</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.2.5(c)</u></font>.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">157</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Reduced Participation and Information
                  Obligations</font>&#8221; means solely with respect to the [***] (a) Biogen may [***], (b) Biogen will [***], (c) Biogen may [***] and (d) Biogen&#8217;s obligation to [***], other than (i) reports required by <font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 5.2.7</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 6.14.1</u></font>&#160;and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>
                    10.4.4</u></font>&#160;(if applicable) (ii) upon Ionis&#8217; reasonable request, information to the extent required to confirm Biogen&#8217;s compliance with its obligations under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 5.1</u></font>&#160;and (iii) as reasonably required to permit Ionis to perform its obligations under this Agreement. The Biogen Reduced Participation and Information Obligations
                will not limit or diminish the scope of any licenses granted by Biogen to Ionis under this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Reduced Royalty</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.2(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Results</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8.3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Supported Pass-Through Costs</font>&#8221;
                means [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Technology</font>&#8221; means the Biogen
                Program Technology, Jointly-Owned Program Technology, Biogen Product-Specific Patents and any trademarks described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.6</u></font>, owned, used, developed by, or
                licensed to Biogen or its Affiliates that is necessary or useful to Develop, register, Manufacture or Commercialize a Product.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen&#8217;s FTE Cost</font>&#8221; means the FTE Rate
                applicable to Biogen, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">multiplied</font> by the applicable number of FTEs.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">[***]</font>&#8221; means [***], or any
                alternative splice variants, mutants, polymorphisms and fragments thereof.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Carryover Development Candidate</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1(e)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">158</font></div>
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            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Change of Control</font>&#8221; means, with
                respect to a Party, (a) a merger or consolidation of such Party with a Third Party which results in the voting securities of such Party outstanding immediately prior thereto ceasing to represent at least 50% of the combined voting power of
                the surviving entity immediately after such merger or consolidation, (b) a transaction or series of related transactions in which a Third Party, together with its Affiliates, becomes the owner of 50% or more of the combined voting power of
                such Party&#8217;s outstanding securities, (c) the sale or other transfer to a Third Party of all or substantially all of such Party&#8217;s business to which the subject matter of this Agreement relates or (d) the stockholders or equity holders of
                such Party will approve a plan of complete liquidation of such Party or an agreement for the sale or disposition by such Party of all or a substantial portion of its assets, other than pursuant to the transaction as described above or to an
                Affiliate. Notwithstanding the foregoing, the sale or issuance of shares in exchange for cash for purposes of a <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">bona fide</font> financing will not
                constitute a Change of Control.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Claims</font>&#8221; has the meaning set forth in
                <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Clinical Study</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Clinical Studies</font>&#8221; means a Phase 1 Trial, Phase 2 Trial, Phase 3 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 or other similar marketing application.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Clinical Supplies</font>&#8221; means API and
                finished drug Collaboration Product for use in a Clinical Study.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">CMC</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.13.1(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">CMO</font>&#8221; means a Third Party contract
                manufacturer Manufacturing API, Clinical Supplies or Finished Drug Product for any purpose under this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaboration</font>&#8221; means the conduct of
                the Neurology Plans in accordance with this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaboration Divestiture Period</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>12.5.3(a)(ii).</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaboration Product</font>&#8221; means, on a
                Collaboration Program-by-Collaboration Program basis, a finished drug product containing a Compound as an active pharmaceutical ingredient.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaboration Program</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.6.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaboration Target</font>&#8221; means a gene
                target for which the Parties wish to start an ASO drug discovery program that is either (i) a High Interest Target that is not an ALS Target and is designated as a Collaboration Target under <font style="font-size: 10pt; font-family:
                  'Times New Roman';"><u>Section 1.3</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8</u></font>, (ii) an ALS Target designated as a Collaboration Target under <font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>Section 1.5</u></font>, (iii) an Ionis Neurology Target designated as a Collaboration Target under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.4</u></font>, (iv) a
                Biogen Alternate Modality Target that is changed to a Collaboration Target under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.1</u></font>, or (v) a Neurology Target that is added as a Collaboration Target
                under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2.4(a)</u></font>.&#160; As of the Effective Date SOD-1 is a Collaboration Target that is an ALS Target and is not a Multi-Indication Target.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaborator IP</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.1.3(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Collaborator License</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.1.3(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">159</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Commercialize</font>,&#8221; &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Commercialization</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 such Product in the
                applicable country, including conducting pre-and post-Approval activities, including studies reasonably required to increase the market potential of such Product and studies to provide improved formulation and Product delivery, and
                launching and promoting such Product in each country.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Commercializing Party</font>&#8221; means (a)
                Biogen, with respect to a Product that is being Developed and Commercialized by or on behalf of Biogen, its Affiliates or Sublicensees hereunder, and (b) Ionis, with respect to a Discontinued Collaboration Product that is being Developed
                and Commercialized by or on behalf of Ionis, its Affiliates or Sublicensees hereunder.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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. Without limiting any of the foregoing, Commercially Reasonable Efforts as it applies to Biogen&#8217;s Development or Commercialization of a Product hereunder includes the
                use of Commercially Reasonable Efforts to perform (i) any Biogen Activities in a Neurology Plan, and (ii) the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">General Activities</font>&#8221; described in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 5.1.4</u></font>, and Commercially Reasonable Efforts as it applies to Ionis&#8217; Development of a Product hereunder includes use of Commercially
                Reasonable Efforts to adhere to the activities and timelines set forth in each Neurology Plan.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Communications Lead</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competing Alternate Modality Acquirer</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.5.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competing Collaboration Acquirer</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.5.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competing Development Activities</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.6</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competitive Indication Product</font>&#8221; means
                any product intended for use in the same indication as any Development Candidate or Collaboration Product.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competitive Indication Program</font>&#8221; means
                any internal research program for which a budget has been established or to which research personnel have been assigned, with the goal of discovering and developing a Competitive Indication Product for which drug discovery activities have
                been initiated.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competitive Infringement</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.5.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">160</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competitive Collaboration Product</font>&#8221;
                means any Oligonucleotide that is designed to bind to or directly modulate the RNA that encodes a High Interest Target or Collaboration Target, other than a Collaboration Product that is being pursued under this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Competitive Collaboration Program</font>&#8221;
                means any internal research program for which a budget has been established or to which research personnel have been assigned, with the goal of discovering and developing a Competitive Collaboration Product for which drug discovery
                activities have been initiated.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Compound</font>&#8221; means, on a Collaboration
                Program-by-Collaboration Program basis, any ASO that is designed to bind to the RNA that encodes the applicable Collaboration Target, where such ASO is discovered by Ionis prior to or in the performance of any Neurology Plan, including each
                Development Candidate under any such Collaboration Program.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Confidential Information</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.1</u></font>. &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">Confidential Information</font>&#8221; does not
                include information that:</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zccb8270db57c4b078f676c4e625e993b">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf737f1a4904448fd96b154185b389bb4">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf53ef4ee80da4adba56f91b1c664acb4">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8dd47a7b5c0a48b2ac1979f237a86ba0">

                    <tr>
                      <td style="width: 36pt;"><br>
                      </td>
                      <td style="width: 45pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">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.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Conflicting Patent Right</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.2.5(d)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Contracting Party</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.7</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Control</font>&#8221; or &#8220;<font style="font-size:
                  10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Third Party Compensation</font>&#8221;) (other than
                Ionis Supported Pass-Through Costs in the case of Ionis, and other than Biogen Supported Pass-Through Costs in the case of Biogen), then the first Party will be deemed to have &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman';
                  font-style: italic;">Control</font>&#8221; of the relevant item of intellectual property only if the other Party agrees to bear the applicable Third Party Compensation. Notwithstanding anything to the contrary under this Agreement, with respect
                to any Third Party acquirer of a Party that becomes an Affiliate of a Party after the Effective Date, no intellectual property of such Third Party acquirer will be included in the licenses granted hereunder by virtue of such Third Party
                becoming an Affiliate of such Party.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">161</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Core Research Plan</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Core Research Program</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Cost Estimate</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(e)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Cover</font>,&#8221; &#8220;<font style="font-size:
                  10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Covered</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Covering</font>&#8221; means, with respect
                to a patent, that, but for rights granted to a Person under such patent, the act of making, using or selling by such 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">CSC</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">CTD</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Deferral Notice</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Deferral Period</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Deferred Target</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Deferred Target Development Candidate</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#8221;</font> means a Development Candidate identified in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.8.4</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;">.</font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Deficiency Notice</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Design Notice</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.2.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Develop</font>,&#8221; &#8220;<font style="font-size:
                  10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Developing</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 such 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 such Product to seek Approval for additional indications
                for such Product.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Development Candidate</font>&#8221; means a
                Compound that is reasonably determined by Ionis&#8217; RMC in accordance with Ionis&#8217; standard procedures for designating development candidates [***] as ready to start IND-Enabling Toxicology Studies; <font style="font-size: 10pt; font-family:
                  'Times New Roman'; font-style: italic;">provided, however</font>, that with respect to any Primarily Neuro Multi-Indication Target, such Compound will be reasonably selected by Biogen (giving good faith consideration to the input of
                Ionis&#8217; representatives on the Neurology JRC) as a Development Candidate from the body of work Ionis used to determine the applicable Compound Ionis believes is ready to start IND-Enabling Toxicology Studies. The checklist Ionis uses as of
                the Effective Date when reviewing potential development candidates for approval is attached hereto as <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 2</u></font>.</font></div>
            <div><br>
            </div>
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            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Development Candidate Data Package</font>&#8221;
                means, with respect to a [***], the [***]; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> such package contains [***]. The checklist Ionis uses as of the Effective Date when reviewing
                potential development candidates for approval is attached hereto as <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Diagnostic Option</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.3.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Directly Competitive Biogen Alternate
                  Modality Product</font>&#8221; means with respect to a Biogen Alternate Modality Product, a product designed to bind to or directly modulate the Biogen Alternate Modality Target targeted by such Biogen Alternate Modality Program, other than a
                Biogen Alternate Modality Product that is being pursued under this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Directly Competitive Biogen Alternate
                  Modality Program</font>&#8221; means any internal research program for which [***] or [***], with the goal of discovering and developing a Directly Competitive Biogen Alternate Modality Product for which drug discovery activities have been
                initiated.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Directly Competitive Collaboration Product</font>&#8221;
                means with respect to a Collaboration Product, any product, other than such Collaboration Product, that is designed to bind to or directly modulate the Collaboration Target targeted by such Collaboration Product.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Directly Competitive Collaboration Program</font>&#8221;
                means any internal research program for which [***] or [***], with the goal of discovering and developing a Directly Competitive Collaboration Product for which drug discovery activities have been initiated.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Disclosing Party</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Discontinued Collaboration Product</font>&#8221;
                means a Collaboration Product that is the subject of a termination under this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Dispute</font>&#8221; means any dispute arising
                between the Parties relating to, arising out of or in any way connected with this Agreement or any term or condition hereof, or the performance by either Party of its obligations hereunder, whether before or after termination of this
                Agreement that cannot be resolved by the Parties.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">DMPK Agreement</font>&#8221; means the DMPK
                Research, Development, Option and License Agreement between the Parties dated June 27, 2012, as amended and/or restated from time to time.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">DOJ</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.4(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Drug Development Program</font>&#8221; means the
                aggregate drug development activities related to each Development Candidate through completion of the first Phase 2 PoC Trial under a Collaboration Program in accordance with the applicable Initial Development Plan for all Collaboration
                Programs under this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Effective Date</font>&#8221; has the meaning set
                forth in the Preamble of this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">EMA</font>&#8221; means the European Medicines
                Agency and any successor entity thereto.</font></div>
            <div><br>
            </div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Enabled Core Program Patents</font>&#8221; means
                Program Patents Controlled by a Party or any of its Affiliates on the Effective Date or during the Agreement Term claiming (a) methods of dosing (frequency, duration, concentration, volume, etc.) generally applicable to Oligonucleotides to
                achieve optimal tissue distribution or enhance other properties of an Oligonucleotide; (b) methods of determining an effective human dose based on animal data that are generally applicable to Oligonucleotides; (c) methods of determining an
                effective dose based on actual or modeled pharmacokinetic data generally applicable to Oligonucleotides; (d) methods of identifying or optimizing predictive biomarkers for diseases; (e) observations about a disease based on data from a
                natural history study; (f) proprietary disease models; or (g) methods of using radio-labeled ligands with Oligonucleotides in animals.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Equal Multi-Indication Target</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Estimated Biogen-Approved Costs</font>&#8221;
                means Ionis&#8217; good faith estimate of the Biogen-Approved Costs it will incur during the applicable Measurement Period.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Estimated Lock Date</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">European Union</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">EU</font>&#8221; means each and every country or territory that is officially part of the European Union.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Excluded Payments</font>&#8221; means (i) royalty
                or profit sharing payments, or any other type of payment based on periodic sales of a Collaboration Product or Deferred Target Development Candidate; (ii) payments made in consideration of Ionis&#8217; or Ionis&#8217; Affiliate&#8217;s equity or debt
                securities at fair market value; (iii) payments made to pay for or reimburse Ionis or Ionis&#8217; Affiliate for the fully-burdened cost of research and development; (iv) payments made to pay for or reimburse Ionis or Ionis&#8217; Affiliate for the
                cost of prosecuting, maintaining or defending Patent Rights; and (v) payments made to Ionis or Ionis&#8217; Affiliate to pass-through to a Third Party in satisfaction of a payment obligation Ionis or Ionis&#8217; Affiliate has to such Third Party.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Executives</font>&#8221; has the meaning set forth
                in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">FDA</font>&#8221; means the United States Food and
                Drug Administration and any successor entity thereto.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">&#8220;[***]&#8221;</font> means any form of the [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">[***] Collaboration Program</font>&#8221; means an
                [***] Collaboration Program solely and exclusively focused on [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Field</font>&#8221; means, except as may be
                limited under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.5</u></font>, any prophylactic or therapeutic use or form of administration for any indication.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Finished Drug Product</font>&#8221; means any drug
                product containing API as an active ingredient in finished bulk form for the Development or Commercialization by a Party under this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">First</font>&#160;<font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Amended and Restated Agreement</font>&#8221; has the meaning set forth in the Preamble of this Agreement.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">164</font></div>
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            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">First</font>&#160;<font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Amendment Date</font>&#8221; has the meaning set forth in the Preamble of this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">First Commercial Sale</font>&#8221; means with
                respect to a Product, the first sale of such Product by Biogen, its Affiliate or its Sublicensee to a Third Party in a particular country after Approval of the Product has been obtained in such country.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Follow-On Agreement</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Follow-On Compound</font>&#8221; means, with
                respect to a given Compound for a given Collaboration Target, any ASO (other than the Development Candidate for such Collaboration Target) that is designed to bind to the RNA that encodes such Collaboration Target discovered by or on behalf
                of Ionis following the License Effective Date for the applicable Collaboration Program.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Follow-On Interest Notice</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Follow-On Negotiation Notice</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">FTC</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.4(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">FTE</font>&#8221; means a total of 47 weeks or
                1880 hours per year of work on the Development, Manufacturing or Commercialization of a Product carried out by employees of a Party having the appropriate relevant expertise to conduct such activities.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">FTE Costs</font>&#8221; has the meaning set forth
                in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">FTE Rate</font>&#8221; means $[***] for the
                Calendar Year 2013. The FTE Rate will be increased each Calendar Year thereafter by the [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Full Royalty Period</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.2(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Fully Absorbed Cost of Goods</font>&#8221; means
                the costs incurred by Ionis as determined using the methodology set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times
                  New Roman';"><u>4.8.2(c)</u></font> fairly applied and as employed on a consistent basis throughout Ionis&#8217; operations<font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;">.</font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">GAAP</font>&#8221; means generally accepted
                accounting principles in the United States, consistently applied.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Gene-Editing Product</font>&#8221; means an
                Oligonucleotide that, when introduced into a cell of an organism, (a) is stably integrated within the genome or stable episome of the cell of such organism or (b) causes (or is perceived to cause) a permanent change in the genome of the
                cell of such organism.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Generic Product</font>&#8221;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>means, with respect to a particular Collaboration Product, one or more Third Party product(s) (i) having the same active pharmaceutical ingredient as such
                Collaboration Product and for which in the U.S. an ANDA has been filed naming such Collaboration Product as the reference listed drug or outside of the U.S., an equivalent process where bioequivalence to such Collaboration Product has been
                asserted, and (ii) such Third Party product(s) when taken in the aggregate have a market share (measured in number of prescriptions with the numerator of such fractional share being such Third Party product(s) taken in the aggregate, and
                the denominator being the total of such Third Party product(s) taken in the aggregate plus such Collaboration Product taken in the aggregate, as provided by IMS) during the applicable Calendar Quarter in such country of at least [***]%.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">165</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">GLP</font>&#8221; means the then-current good
                laboratory practice standards promulgated or endorsed by the FDA as defined in 21 C.F.R. Part 58, and comparable foreign regulatory standards.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">High Interest Target</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2.3(a)</u></font>.&#160; For clarity, at any given time, if a gene target is not on the High Interest Target List at such time, then such gene target is
                not a High Interest Target.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">High Interest Target List</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2.3(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">HSR Act</font>&#8221; means the Hart-Scott-Rodino
                Antitrust Improvements Act of 1976, as amended, and the rules and regulations promulgated thereunder.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">HSR Clearance</font>&#8221; means all applicable
                waiting periods under the HSR Act with respect to the transactions contemplated under this Agreement have expired or have been terminated.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">HSR Clearance Date</font>&#8221; means the
                earliest date on which the Parties have actual knowledge that all applicable waiting periods under the HSR Act with respect to the transactions contemplated under this Agreement have expired or have been terminated.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">HSR Filing</font>&#8221; means filings by Biogen
                and Ionis with the United States Federal Trade Commission and the Antitrust Division of the United States Department of Justice of a Notification and Report Form for Certain Mergers and Acquisitions (as that term is defined in the HSR Act)
                with respect to the matters set forth in this Agreement, together with all required documentary attachments thereto.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Incremental Tax Cost</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">IND-Enabling Toxicology Studies</font>&#8221;
                means the pharmacokinetic and toxicology studies required to meet the requirements for filing an IND.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Indemnitee</font>&#8221; has the meaning set forth
                in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Initial Development Plan</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(d)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Initiation</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Initiate</font>&#8221; means, with respect to any IND-Enabling Toxicology Study, dosing of the first animal subject in such IND-Enabling Toxicology
                Study and, with respect to any Clinical Study, dosing of the first human subject in such Clinical Study.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Integrated Development Plan</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">IDP</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1.6</u></font>.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">166</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis</font>&#8221; has the meaning set forth in
                the Preamble of this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Activities</font>&#8221; means the research,
                pre-clinical and/or clinical activities for which Ionis is designated as responsible under any Neurology Plan.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Activities Data</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(d)(i)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Attribution Language</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4.11</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight:
                  bold; font-style: italic;">Ionis/Biogen Additional Agreements</font><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8221; means the (i) SMN Agreement, (ii) DMPK Agreement</font><font style="font-size: 10pt; font-family: 'Times
                  New Roman';">, (iii) the </font>Neurology Drug Discovery and Development Collaboration, Option and License Agreement between the Parties dated December 10, 2012, (iv) the Research Collaboration, Option and License Agreement between the
                Parties dated December 19, 2017 and (v) the Neurology III Agreement, in each case, as amended and/or restated from time to time</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Breach Event</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.5(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Core Technology Patents</font>&#8221; means
                all Patent Rights owned, used, developed by, or licensed to Ionis or its Affiliates, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term, claiming subject matter
                generally applicable to ASOs, other than Ionis Product-Specific Patents or Ionis Manufacturing and Analytical Patents. A list of Ionis Core Technology Patents as of the Effective Date is set forth on <font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 8.2.4(a)</u></font> attached hereto.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis In-License Agreements</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.13.1(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Internal ASO Safety Database</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.2.7</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Know-How</font>&#8221; means any Know-How,
                including any Jointly-Owned Program Know-How and Ionis Program Know-How, owned, used, developed by, or licensed to Ionis or its Affiliates, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any
                time during the Agreement Term. Ionis Know-How does not include the Ionis Manufacturing and Analytical Know-How.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Manufacturing and Analytical Know-How</font>&#8221;
                means Know-How, including Jointly-Owned Program 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 Ionis or its Affiliates, in each
                case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term. Ionis Manufacturing and Analytical Know-How does not include the Ionis Know-How.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Manufacturing and Analytical Patents</font>&#8221;
                means Patent Rights, including Jointly-Owned Program 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 Ionis
                or its Affiliates, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term. A list of Ionis Manufacturing and Analytical Patents as they related to ASOs as of the
                Effective Date is set forth on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 8.2.4(b)</u></font> attached
                hereto. Ionis Manufacturing and Analytical Patents do not include the Ionis Product-Specific Patents or the Ionis Core Technology Patents.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">167</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Multi-Indication Compound</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Neurology Target</font>&#8221; means a
                Neurology Target that (1) is not (i) a High Interest Target for which target validating activities are planned under the then-current Neurological Disease Research Plan, (ii) an ALS Target, (iii) a Collaboration Target, or (iv) a Biogen
                Alternate Modality Target and (2) has a Neurological Disease as its primary disease association.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Non-Exclusive Product</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.1.1(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Platform Technology</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.2.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Product-Specific Patents</font>&#8221; means
                all Product-Specific Patents, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term. A list of Ionis Product-Specific Patents as of the Effective Date is set forth on
                <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 8.2.4(c)</u></font> attached hereto.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Program Know-How</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Program Patents</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Program Technology</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Results</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8.3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Supported Pass-Through Costs</font>&#8221;
                means [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Japan NDA</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">JNDA</font>&#8221; means the Japanese equivalent of an NDA filed with the Koseisho (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">,</font> the Japanese Ministry of Health and Welfare, or any successor agency thereto).</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">JNDA Approval</font>&#8221; means the Approval of
                a JNDA by the Koseisho (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">,</font> the Japanese Ministry of Health and
                Welfare, or any successor agency thereto) for the applicable Product in Japan.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Joint Patent Committee</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">JPC</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.3(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Jointly-Owned Program Know-How</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Jointly-Owned Program Patents</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Jointly-Owned Program Technology</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Know-How</font>&#8221; means 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, in each case whether or not patentable or copyrightable, and in each case that are unpatented.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">168</font></div>
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            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Lead Party</font>&#8221; has the meaning set forth
                in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.4.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">License Effective Date</font>&#8221; means, on an
                Option-by-Option and Program-by-Program basis, the date on which Biogen notifies Ionis in writing that it wishes to exercise the Option and pays to Ionis the applicable license fee set forth in <font style="font-size: 10pt; font-family:
                  'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 6.6</u></font>&#160;(in the event Biogen wishes to exercise its Option for a Collaboration Program) or <font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 6.2.2</u></font>&#160; (in the event Biogen wishes to exercise its Option for a Biogen Alternate Modality Program) for
                such Program.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Licensed Know-How</font>&#8221; means Ionis
                Manufacturing and Analytical Know-How, and Ionis Know-How. For clarity, Licensed Know-How does not include any Know-How covering formulation technology or delivery devices.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Licensed Patents</font>&#8221; means the Ionis
                Product-Specific Patents, Ionis Core Technology Patents, Ionis Manufacturing and Analytical Patents and Ionis&#8217; interest in Jointly-Owned Program Patents. For clarity, Licensed Patents do not include any Patent Rights claiming formulation
                technology or delivery devices unless such Patent Rights are included in the Jointly-Owned Program Patents.&#160; For clarity, Licensed Patents that are jointly-owned by Ionis and Biogen 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Licensed Technology</font>&#8221; means, on a&#160;
                Program-by- Program basis, any and all Licensed Patents, Licensed Know-How, and any trademarks described in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.6</u></font>, to the extent necessary or useful to
                Develop, register, Manufacture or Commercialize such Product.&#160; Licensed Technology does not include any technology in-licensed by Ionis from [***] under the [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Losses</font>&#8221; has the meaning set forth in
                <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 9.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">MAA</font>&#8221; means, with respect to a
                particular Product, a marketing authorization application filed with the EMA or other European Regulatory Authority after completion of Clinical Studies to obtain Approval for such Product under the centralized European filing procedure or,
                if the centralized EMA filing procedure is not used, filed using the applicable procedures in any European Union country or other country in Europe.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">MAA Approval</font>&#8221; means, with respect to
                a particular Product, the Approval of an MAA by the EMA for such Product in any European Union country or other country in Europe.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Major Market</font>&#8221; means any of the
                following countries: the United States, Japan, the United Kingdom, Germany, France, Italy and Spain.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Manufacture</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Manufactured</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 the bulk active
                pharmaceutical ingredient for a Biogen Alternate Modality Product, or a Collaboration Product or Biogen Alternate Modality Product in finished form.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Manufacturing Process Development Terms</font>&#8221;
                means <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1.3(b)</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times
                  New Roman';"><u>4.3.1(a)</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.2</u></font>, <font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 4.4</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.5</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.7.2</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                  </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8.3</u></font> of this Agreement.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">169</font></div>
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            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Measurement Period</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1(c)</u></font> or <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.14.1(d)</u></font>, as applicable.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Milestone Event</font>&#8221; means a Biogen
                Alternate Modality Milestone Event, a Pre-Licensing Milestone Event or a Post-Licensing Milestone Event, as the case may be.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Minimum Third Party Payments</font>&#8221; means
                [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">[***]</font>&#8221; means a disease that has, as
                its [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Multi-Indication Product</font>&#8221; means a
                product for a Non-Neurological Indication associated with a Multi-Indication Target.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Multi-Indication Product-Specific Patent</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.2.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Multi-Indication Target</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2.3(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Multi-Indication Target Notice</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2.3(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">NDA</font>&#8221;<font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-weight: bold;">&#160;</font>means a New Drug Application filed with the FDA after completion of Clinical Studies to obtain Approval for a Product in the United States.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">NDA Approval</font>&#8221; means the Approval of
                an NDA by the FDA for a Product in the U.S.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Negotiation Period</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Net Sales</font>&#8221; means the gross amount
                billed or invoiced on sales of a Product by Biogen, its Affiliates and Sublicensees, less the following: (a) customary trade, quantity, or cash discounts to non-affiliated brokers or agents to the extent actually allowed and taken; (b)
                amounts repaid or credited by reason of rejection or return; (c) to the extent separately stated on purchase orders, invoices, or other documents of sale, any taxes or other governmental charges levied on the production, sale,
                transportation, delivery, or use of such Product which is paid by or on behalf of Biogen; and (d) outbound transportation costs prepaid or allowed and costs of insurance in transit.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">In any transfers of a Product between Biogen, its Affiliates and Sublicensees, Net Sales are calculated based on the final sale of such Product to
                an independent Third Party. If Biogen, its Affiliate or a Sublicensee receives non-monetary consideration for a Product, Net Sales are calculated based on the fair market value of that consideration. If Biogen, its Affiliates or
                Sublicensees uses or disposes of a Product in the provision of a commercial service, the Product is sold and the Net Sales are calculated based on the sales price of the Product to an independent Third Party during the same royalty period
                or, in the absence of sales, on the fair market value of the Product as determined by the Parties in good faith. Net Sales will not include any transfers of supplies of the applicable Product for (i) use in clinical trials, Pre-Clinical
                Studies or other research or development activities, or (ii) a <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">bona fide</font> charitable purpose; or (iii) a commercially reasonable sampling program.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">170</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">With respect to Net Sales as it applies to royalties payable by Ionis, the Parties agree that any reasonable definition of &#8220;net sales&#8221; that is (x)
                customarily used in pharmaceutical industry technology licensing or collaboration contracts and (y) consistent with GAAP or International Financial Reporting Standards and is subsequently agreed to by Ionis (or a Third Party acquirer or
                assignee) and Ionis&#8217; Sublicensee or commercialization partner in an arms-length transaction under a particular sublicense or commercialization agreement will replace the definition of Net Sales in this Agreement and will be used in
                calculating the royalty payment to Biogen on sales of products sold pursuant to such agreement. If Ionis uses such an alternate definition of &#8220;net sales&#8221; in a particular sublicense, (A) Ionis will include such &#8220;net sales&#8221; definition in the
                applicable royalty reports to assist Biogen with verifying royalty payments and (B) if such definition is not consistent with GAAP or International Financial Reporting Standards, upon Biogen&#8217;s request, Ionis will reconcile the royalties
                calculated under such definition with GAAP or International Financial Reporting Standards.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurological Disease Research Plan</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurological Disease Research Program</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurology III Agreement</font>&#8221; means that
                certain New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement between the Parties dated April 19, 2018, as amended or restated from time to time.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurology JDC</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurology JRC</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurology Plan</font>&#8221; means any of the
                following plans: (i) the Core Research Plan, (ii) the Neurological Disease Research Plan, (iii) any ASO Development Candidate Identification Plans, or (iv) any Initial Development Plans.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurology Target</font>&#8221; means any gene
                target that (i) as of the Effective Date, (y) has not been encumbered by Ionis under an agreement with a Third Party that would prevent Ionis from granting Biogen the license under <font style="font-size: 10pt; font-family: 'Times New
                  Roman';"><u>Section 4.1.1</u></font> of this Agreement with respect to such gene target, and (z) has not yet achieved Target Sanction status, and (ii) as of the Effective Date or during the Research Term, the expression or activity of the
                gene in neurons is demonstrated to have an association to any one of the following (each of (a) through (e) below, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurological Disease</font>&#8221;):</font></div>
            <div><br>
            </div>
            <div style="text-align: justify; margin-left: 18pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">For purposes of clarity, [***] are expressly excluded from the above-listed [***] and therefore any gene target that has as its primary disease
                association an association to [***] will not be a Neurology Target, and any [***] will not be a Product under this Agreement. In addition, [***] or [***] are expressly excluded from the above-listed [***] and therefore any gene target that
                has as its [***] will not be a Neurology Target.&#160; For purposes of further clarity, a gene target that has as its [***] would not be considered a Neurology Target.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">New Third Party Licenses</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 8.3.2</u></font>.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">171</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Non-Neurological Indications</font>&#8221; means
                therapeutic uses that are not designed to treat neurological diseases or [***] diseases.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">NPV</font>&#8221; has the meaning set forth in&#160;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;">.</font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">[***]</font>&#8221; means diseases that have, as
                their [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Oligonucleotide</font>&#8221; means a synthetic
                compound that comprises or consists of at least 5 linked nucleosides (including any analog, variant, mimic, or mimetic thereof). For clarity, the [***] of Oligonucleotides [***].&#160; Oligonucleotides [***].&#160; Oligonucleotides may be
                single-stranded or multi-stranded.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option</font>&#8221; has the meaning set forth in
                <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Acceleration Deadline</font>&#8221;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">&#160;</font>has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(g)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Acceleration Notice</font>&#8221;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">&#160;</font>has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.2(g)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">&#8220;Option Deadline&#8221;</font> means the Standard
                Option Deadline, the ALS Option Deadline or the Biogen Conducted Non-ALS Option Deadline, as applicable.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Period</font>&#8221; means, with respect to
                a Collaboration Program, the period beginning on the date a Neurology Target is designated as a Collaboration Program hereunder and ending on the License Effective Date or the expiration or earlier termination of the Option with respect to
                such Collaboration Program.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Original Agreement</font>&#8221; has the meaning
                set forth in the Preamble of this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Panel Decision</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.5(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Party</font>&#8221; or &#8220;<font style="font-size:
                  10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Parties</font>&#8221; means Biogen and Ionis individually or collectively.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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).</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">172</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Permitted Licenses</font>&#8221; means (1)
                licenses granted by Ionis before or after the Effective Date to any Third Party under the Ionis Core Technology Patents, the Ionis Manufacturing and Analytical Patents, or the Ionis Manufacturing and Analytical Know-How (but not under the
                Ionis 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 (i) such Third
                Party is primarily engaged in providing contract manufacturing or services and is not primarily engaged in drug discovery, development or commercialization of therapeutics; and (ii) Ionis 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 non-commercial research.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pharmacovigilance Agreement</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.2.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Phase 1 Trial</font>&#8221; means the first
                clinical study in human beings Initiated by Ionis or Biogen under the applicable Initial Development Plan pursuant to an IND that has been filed with a Regulatory Authority in a Major Market or Canada. If Biogen exercises the Option before
                Ionis Initiates such a Phase 1 Trial for a given Development Candidate, then the definition of <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#8220;</font><font style="font-size: 10pt; font-family: 'Times New
                  Roman'; font-weight: bold; font-style: italic;">Phase 1 Trial</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">&#8221;</font> means the first clinical study of the applicable Development Candidate in human
                beings Initiated by Biogen, its Affiliate or its Sublicensee.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Phase 1 Trial Design</font>&#8221; means, with
                respect to a Collaboration Program, the Phase 1 Trial design set forth in the applicable Initial Development Plan, which may be amended from time to time during the Agreement Term as mutually agreed in writing by the Parties (in
                consultation with the Neurology JDC).</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Phase 2 Trial</font>&#8221; means, with respect to
                a Product, a Clinical Study that is intended to explore the feasibility, safety, dose ranging or efficacy of such Product, that is prospectively designed to generate sufficient data (if successful) to commence a Phase 3 Trial (or foreign
                equivalent) of such product, as further defined in 21 C.F.R. 312.21(b) or the corresponding regulation in jurisdictions other than the United States.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Phase 3 Trial</font>&#8221; means, with respect to
                a Product, a pivotal Clinical Study in humans performed to gain evidence with statistical significance of the efficacy of such product in a target population, and to obtain expanded evidence of safety for such product that is needed to
                evaluate the overall benefit-risk relationship of such product, to form the basis for approval of an NDA by a Regulatory Authority and to provide an adequate basis for physician labeling, as described in 21 C.F.R. 312.21(c), as amended from
                time to time, or the corresponding regulation in jurisdictions other than the United States.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Phase 4 Trial</font>&#8221; means, with respect to
                a Product, (a) any Clinical Study conducted to satisfy a requirement of a Regulatory Authority in order to maintain a Regulatory Approval for such Product or (b) any Clinical Study conducted after the first Regulatory Approval in the same
                disease state for which such Product received Regulatory Approval other than for purposes of obtaining Regulatory Approval.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">173</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">PoC Data Package</font>&#8221; means, with respect
                to a Collaboration Product, [***], (iv) copies of all filings submitted to Regulatory Authorities regarding such Collaboration Product, (v) a summary of the patent status relating to such Collaboration Product, and (vi) a summary of any
                Third Party Obligations Ionis believes relate to the Collaboration Product.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">PoC Trial</font>&#8221; means, with respect to a
                Collaboration Program, the first phase 2a Clinical Study in human patients with a pharmacokinetic or target reduction endpoint or other therapeutic or physiological endpoint.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">PoC Trial Completion Notice</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">PoC Trial Design</font>&#8221; means the PoC Trial
                design set forth in each Initial Development Plan, which may be amended from time to time during the Agreement Term as mutually agreed in writing by the Parties (in consultation with the Neurology JDC).</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Post-Licensing Milestone Event</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.7</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Clinical Studies</font>&#8221; means <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">in vitro</font> and <font style="font-size: 10pt; font-family: 'Times New Roman'; 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 such Product and whether such Product has a desired effect.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Existing Competitive Collaboration
                  Product</font>&#8221; has the meaning set forth in Section 12.5.2.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Existing Competitive Collaboration
                  Program</font>&#8221; has the meaning set forth in Section 12.5.2.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Existing Target</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#8221;</font> has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2.3(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Licensing Milestone Event</font>&#8221; means
                an ALS Pre-Licensing Milestone Event or a Standard Pre-Licensing Milestone Event, as applicable.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Primarily Neuro Multi-Indication Target</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Primarily Other Multi-Indication Target</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Appendix 3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#160;&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Prior Agreements</font>&#8221; means the
                agreements listed on <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 8.2.8</u></font> attached hereto.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Proceeding</font>&#8221; means an action, suit or
                proceeding.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Product</font>&#8221; means (i) a Biogen Alternate
                Modality Product, or (ii) a Collaboration Product.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Product-Specific Patents</font>&#8221; means, with
                respect to a Product, Patent Rights Controlled by a Party or any of its Affiliates on or after the Effective Date, including any Program Patents, claiming (a) the specific composition of matter of such Product, (b) methods of using such
                Product as a prophylactic or therapeutic or (c) the specific method of manufacture of such Product (unless in the case of (c), such Patent Rights also claim any other product or services of Ionis); <font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-style: italic;">provided however</font>, Patent Rights Controlled by Ionis or any of its Affiliates that (i) include claims that are directed to subject matter applicable to ASOs or products in
                general, or (ii) include an ASO, the sequence of which targets the RNA that encodes a Collaboration Target and the RNA of a gene that does not encode a Collaboration Target (or similarly, a non-ASO molecule that binds, mimics or otherwise
                affects a protein or RNA that is encoded by a Biogen Alternate Modality Target and the RNA of a gene that does not encode a Biogen Alternate Modality Target), will not be considered Product-Specific Patents, and in the case of (i) and (ii),
                such Patent Rights will be considered Ionis Core Technology Patents.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">174</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Program</font>&#8221; has the meaning set forth in
                <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 7.2.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Program Patents</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Prosecution and Maintenance</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Prosecution and Maintenance</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times
                  New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">[***]</font>&#8221; means a [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Receiving Party</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Reduced Royalty Period</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.2(d)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Regulatory Approval</font>&#8221; means the
                approval necessary for the commercial manufacture, distribution, marketing, promotion, offer for sale, use, import, export, and sale of a pharmaceutical product in a jurisdiction regulated by a Regulatory Authority.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Regulatory Authority</font>&#8221; means any
                governmental authority, including the FDA, EMA or Koseisho (<font style="font-size: 10pt; font-family: 'Times New Roman';"><u>i.e.</u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Regulatory Materials</font>&#8221; means, with
                respect to a Product, any regulatory submissions, notifications, registrations, approvals or other filings and correspondence made to or with a Regulatory Authority in any country or jurisdiction, and any other records required by
                Applicable Law to be maintained that may be necessary or useful to develop, manufacture, market, sell or otherwise commercialize such Product in any such country or jurisdiction.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Research</font>&#8221; means conducting the
                research activities with ASOs or Compounds as set forth in the Neurology Plans, including pre-clinical research and lead optimization, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">but specifically
                  excluding</font> Development and Commercialization. When used as a verb, &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Researching</font>&#8221; means to engage in Research.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Research Term</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.2.1</u></font>.</font></div>
            <div><br>
            </div>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">175</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Results</font>&#8221; has the meaning set forth in
                <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8.3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Reverse Royalties</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.12.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">RMC</font>&#8221; means Ionis&#8217; Research Management
                Committee, or any successor committee.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">ROFN Period</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 2.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Royalty Quotient</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.10.2(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Second</font>&#160;<font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Amendment Date</font>&#8221; has the meaning set forth in the Preamble of this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Service Provider</font>&#8221; means the Third
                Party(ies) conducting the original and revised studies under the applicable Initial Development Plan.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Setoff Amount</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.5(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Setoff Dispute</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.5(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Setoff Dispute Notice</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.5(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">SMN Agreement</font>&#8221; means the Development,
                Option and License Agreement between the Parties dated January 3, 2012, as amended and/or restated from time to time.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Specific Performance Milestone Events</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#8220;</font><font style="font-size: 10pt; font-weight: bold;
                  font-style: italic;">[***]</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#8221;</font> means the form of the [***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#8220;</font><font style="font-size: 10pt; font-weight: bold;
                  font-style: italic;">Standard</font><font style="font-weight: bold; font-style: italic;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Option Deadline</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1.3</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">&#8220;</font><font style="font-size: 10pt; font-weight: bold;
                  font-style: italic;">Standard</font><font style="font-weight: bold; font-style: italic;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Pre-Licensing Milestone Event</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 6.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Step-In Party</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.4.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 Biogen Technology, as the case may be, licensed to such Party in accordance with the terms of this Agreement.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Subsequent Deal</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.2.3(b)(i)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Superior Patent Right</font>&#8221; has the
                meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>7.2.5(d)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Target Related Biogen Program Claim</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Target Related Ionis Program Claim</font>&#8221;
                has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.3.2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Target Sanction</font>&#8221; means when the
                therapeutic potential of a Neurology Target has been demonstrated in pre-clinical disease models and such Neurology Target has received approval by Ionis&#8217; RMC to justify expending resources to identify a human Development Candidate, all in
                accordance with Ionis&#8217; standard processes.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">176</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Target Sanction Data Package</font>&#8221; means,
                with respect to a Neurology Target, the data package Ionis presented to its RMC to obtain approval to justify expending resources to identify a human Development Candidate, all in accordance with Ionis&#8217; standard processes; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font> such package contains the same level of detail as the data packages Ionis currently presents to its Research Management Committee to approve
                Ionis&#8217; own internal gene targets.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Technical Failure</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.10.1(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Third Party</font>&#8221; means a Person or entity
                other than the Parties or their respective Affiliates.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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 Ionis and a Third Party (including the Ionis In-License Agreements) that relate to a Product, Biogen Alternate Modality
                Target or a Collaboration Target, including field or territory restrictions, covenants, milestone payments, diligence obligations, sublicense revenue, royalties, or other payments.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Transition Services</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.6</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Trial Court</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 10.4.5(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">United States</font>&#8221; or &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; 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.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Valid Claim</font>&#8221; means a claim (a) of any
                issued, unexpired United States or foreign Patent Right, which will not, in the country of issuance, have been donated to the public, disclaimed, nor held invalid or unenforceable by a court of competent jurisdiction in an unappealed or
                unappealable decision or (b) of any United States or foreign patent application within a Patent Right, which will not, in the country in question, have been cancelled, withdrawn, abandoned nor been pending for more than seven years, not
                including in calculating such seven-year period of time in which such application is in interference or opposition or similar proceedings or time in which a decision of an examiner is being appealed. Notwithstanding the foregoing, on a
                country-by-country basis, a patent application pending for more than seven years will not be considered to have any Valid Claim for purposes of this Agreement unless and until a patent meeting the criteria set forth in clause (a) above with
                respect to such application issues.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">177</font></div>
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            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Appendix 2</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Development Candidate Checklist</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">178</font></div>
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            <!--PROfilePageNumberReset%Num%179%%%-->
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Appendix 3</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Multi-Indication Target Process</font></div>
            <div><br>
            </div>
            <div style="text-align: justify; text-indent: -36pt; margin-left: 72pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Neurology Targets with
                    Broader Therapeutic Benefit</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5923b24a70014dd7a10d6ef553f81a17">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div style="text-indent: 9pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">If, pursuant to <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 1.2.3(d)</u></font>, the
                            CSC is unable to agree upon whether a Multi-Indication Target is a Primarily Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other Multi-Indication Target, the Parties will engage an expert panel under
                            <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 12.1.4</u></font> to make such determination. Such expert panel will first determine the net present value (&#8220;<font style="font-size: 10pt;
                              font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">NPV</font>&#8221;) of a therapeutic targeting such Multi-Indication Target and allocate such NPV between the markets for Neurological Disease
                            indications and for Non-Neurological Indications, where such NPV calculations and allocations will take into consideration, and risk-adjust for, the relevant market sizes, competitive landscapes, scientific rationale for each
                            market and any other factors deemed relevant by such expert panel.&#160; Based on such NPV calculations and allocations, Multi-Indication Targets will be classified as either <font style="font-size: 10pt; font-family: &quot;Times
                              New Roman&quot;; font-weight: bold; font-style: italic;">&#8220;Primarily Neuro Multi-Indication Targets&#8221;</font>; <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">&#8220;Equal






                              Multi-Indication Targets&#8221;</font> or <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">&#8220;Primarily Other Multi-Indication Targets&#8221;</font>, where (1) a
                            Multi-Indication Target with [***]% or more of its NPV allocated to the market for Neurological Disease indications will be a Primarily Neuro Multi-Indication Target, (2) a Multi-Indication Target with less than [***]% but more
                            than [***]% of its NPV allocated to the market for Neurological Disease indications will be an Equal Multi-Indication Target, and (3) a Multi-Indication Target with [***]% or less of its NPV allocated to the market for
                            Neurological Disease indications will be Primarily Other Multi-Indication Target.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
          </div>
          <div>
            <div style="text-align: justify;">
              <div>
                <div><br>
                </div>
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                  <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">179</font></div>
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                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z5353beb13a804ce4a718381fb543758c">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right; font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">&#160;(b)</td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div style="text-indent: 9pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><u>Primarily Neuro Multi-Indication
                                Targets</u></font>.<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">&#160; </font>If a Multi-Indication Target is classified as a Primarily Neuro Multi-Indication Target, then within
                            [***] days of such classification, Biogen will send Ionis a written notice either (1) electing to negotiate in good faith with Ionis a development plan and [***] (<font style="font-size: 10pt; font-family: &quot;Times New
                              Roman&quot;;"><u>i.e.</u></font>, [***]) for the Non-Neurological Indications if Developed and Commercialized under this Agreement, which plan and provisions will be recommended to the CSC for approval; (2) granting Ionis and
                            its Affiliates the right to work on their own or with a Third Party to discover, develop and commercialize an Oligonucleotide against such Multi-Indication Target for primarily Non-Neurological Indications (an &#8220;<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">Ionis Multi-Indication Compound</font>&#8221;); or (3) precluding Ionis and its Affiliates from working on their own or with a
                            Third Party to discover, develop commercialize an Ionis Multi-Indication Compound.&#160; If under this clause (b) Ionis or any of its Affiliates or licensees Commercializes a product incorporating an Ionis Multi-Indication Compound,
                            and Biogen has paid the applicable license fee under <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Section 6.6</u></font> for the applicable Collaboration Program, then until the earlier of (i) the
                            [***] anniversary of the date of First Commercial Sale of such product or (ii) the date Biogen, its Affiliates and Sublicensees stop Commercializing the Product related to such Multi-Indication Target, Ionis will pay Biogen a
                            royalty of [***]% of Annual worldwide Net Sales of such product sold by Ionis, its Affiliates or Sublicensees. The definition of Net Sales in <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant:
                              small-caps;"><u>Appendix 1</u></font> and the other provisions contained in <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Sections 6.14</u></font>, <font style="font-size: 10pt; font-family:
                              &quot;Times New Roman&quot;;"><u>6.15</u></font>, <font style="font-size: 10pt;"><u>6.16</u></font>, and <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>6.17</u></font> governing payment of
                            royalties from Biogen to Ionis will govern the payment of such royalty from Ionis to Biogen under this clause (b), <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;">mutatis mutandis</font>.&#160;






                            If within [***] days of Biogen making an election under clause (1) of this clause (b) to pursue the Non-Neurological Indication, the CSC has not agreed on a development plan and enhanced economic provisions to be paid by Biogen
                            for the Non-Neurological Indication, then (I) Ionis and its Affiliates will not work on their own or with a Third Party to discover, develop and commercialize in the Field an Ionis Multi-Indication Compound unless otherwise
                            permitted under this Agreement and (II) Biogen and its Affiliates will not work on their own or with a Third Party to discover, develop or commercialize Compounds related to such Multi-Indication Target for Non-Neurological
                            Indications.</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z733fb248eec14e32b6f09ca68161a485">

                    <tr>
                      <td style="width: 81pt;"><br>
                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div style="text-indent: 9pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><u>Equal Multi-Indication Targets</u></font>.
                            If a Multi-Indication Target is classified as an Equal Multi-Indication Target, neither Party nor its respective Affiliates, licensees or Sublicensees may develop or commercialize a product targeting such Multi-Indication Target
                            for any indication unless and until Ionis and Biogen have agreed on (i) a development plan and enhanced economic provisions to be paid by Biogen (<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>i.e.</u></font>,
                            multi-indication filing and approval milestone payments, but not additional license fees) for the Non-Neurological Indications, and (ii) the restrictions under which Ionis or Biogen (as applicable) would develop or commercialize
                            a product targeting such Multi-Indication Target (which terms may include the requirements set forth under clause (d)(2) below).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">180</font></div>
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            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z55785ead83e743229d677616dcafde28">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div style="text-indent: 9pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><u>Primarily Other Multi-Indication
                                Targets</u></font>.<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">&#160; </font>If a Multi-Indication Target is classified as a Primarily Other Multi-Indication Target, then (A)
                            Biogen may continue to Develop and Commercialize Products for Neurological Disease indications pursuant to the terms of this Agreement, and (B) within [***] days of such classification, Biogen will send Ionis a written notice
                            either (1) electing to negotiate in good faith with Ionis and agree on a development plan and [***] (<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>i.e.</u></font>, [***]) for the Non-Neurological
                            Indications if Developed and Commercialized under this Agreement, which plan and provisions will be recommended to the CSC for approval; or (2) granting Ionis and its Affiliates the right to work on their own or with a Third
                            Party to discover, develop and commercialize an Ionis Multi-Indication Compound so long as such Ionis Multi-Indication Compound [***], <font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;">provided</font>,
                            in addition to the foregoing provisions, if the Development Candidate targeting such Multi-Indication Target being Developed or Commercialized by Biogen, its Affiliates or Sublicensees under this Agreement is [***], Ionis cannot
                            develop or commercialize such Ionis Multi-Indication Compound for [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z93f7e3c3469c404fb70471d96711775d">

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                      </td>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div style="text-indent: 9pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">If within [***] days of Biogen making an election under clause (b)(1) of this <font style="font-size: 10pt; font-family:
                              &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Appendix 3</u></font> to pursue the Non-Neurological Indication, the CSC has not agreed on a development plan and [***] (<font style="font-size: 10pt; font-family:
                              &quot;Times New Roman&quot;;"><u>i.e.</u></font>, [***]) for the Non-Neurological Indications, then Ionis and its Affiliates will have the right to work on their own or with a Third Party to discover, develop and commercialize
                            an Ionis Multi-Indication Compound so long as such Ionis Multi-Indication Compound [***]<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;">.</font></font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">181</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> </u></font></font>
              <table cellspacing="0" cellpadding="0" border="0" id="zc075b84c4f1e411b9e217e149e2956a8" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;">

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                      <div style="text-align: left;"><img width="164" height="55" src="image10.jpg"></div>
                    </td>
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            </div>
            <u> <br>
            </u>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Appendix 4</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
                  </u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Form of Side Letter</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">[</font><font style="font-size: 10pt; font-style: italic;">Date</font><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">]</font></font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Ionis Pharmaceuticals, Inc.</font></font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">2855 Gazelle Court</font></font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Carlsbad, CA 92010</font></font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Attention:&#160; Chief Operating Officer</font></font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">E-mail: [***]</font></div>
            <div><br>
            </div>
            <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Re:&#160; Establishment of Cost Estimates and Milestone Payments</font></div>
            <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Dear [</font><font style="font-size: 10pt; font-family:
                  'Times New Roman'; font-style: italic;">Chief Operating Officer</font><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">]:</font></font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">&#160; <br>
                </font></font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Reference is hereby made to that
                  certain </font>Second<font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and
                  between Ionis and Biogen dated _________ ___, [</font>2018] (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Neurology II Agreement</font>&#8221;<font style="background-color: #FFFFFF;
                  font-size: 10pt; font-family: 'Times New Roman';">), as supplemented and/or amended to date.&#160; Any capitalized terms not defined herein will have the meaning set forth in the Neurology II Agreement.</font></font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">&#160; <br>
                </font></font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">This letter memorializes the Cost
                  Estimates and corresponding milestone payments set forth on the exhibit attached hereto as </font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Exhibit A</u></font><font style="background-color: #FFFFFF; font-size:
                  10pt; font-family: 'Times New Roman';"> for the Collaboration Program and Development Candidate specified on </font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Exhibit A</u></font><font style="background-color:
                  #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">, which Cost Estimates and corresponding milestone payments have been agreed by the applicable Neurology JDC in accordance with </font><font style="font-size: 10pt; font-family:
                  'Times New Roman';"><u>Section 1.10.2(e)</u></font><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> of the Neurology II Agreement. </font><font style="font-size: 10pt; font-family: 'Times New
                  Roman';"><u>Exhibit A</u></font><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> hereto supersedes and replaces any previously approved Cost Estimates and corresponding milestone payments for the
                  Collaboration Program and Development Candidate set forth on </font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Exhibit A</u></font><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New
                  Roman';">.</font></font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">&#160; <br>
                </font></font></div>
            <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Please indicate your concurrence with
                  the accuracy of </font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Exhibit A</u></font><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> as agreed to by the applicable
                  Neurology JDC by executing a copy of this letter and returning it to Biogen. This letter may be executed in counterparts, each of which will be deemed an original, notwithstanding variations in format or file designation which may result
                  from electronic transmission, store and printing of copies of this letter from separate computers or printers.&#160; Facsimile signatures and signatures transmitted via electronic mail in PDF format will be treated as original signatures.</font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">[</font><font style="font-size: 10pt; font-style: italic;">The






                  remainder of this page is intentionally left blank.</font><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">]</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">&#160; <br>
                </font></font></div>
            <div style="text-align: center;">
              <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;">225 Binney Street, Cambridge, MA 02142 <font style="font-size: 10pt; font-family: 'Times New Roman';">&#8226;</font> Phone 781-464-2000 &#8226; www.biogen.com</div>
              <div style="text-align: center; font-family: 'Times New Roman'; font-size: 10pt;"> <br>
              </div>
              <font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> </font></font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;"> </font></font>
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                    <td style="width: 50.00%;">
                      <div>&#160;</div>
                    </td>
                    <td style="width: 50.00%;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Sincerely,</font></font></td>
                  </tr>
                  <tr>
                    <td rowspan="1" style="width: 50.00%;">&#160;</td>
                    <td rowspan="1" style="width: 50.00%;">&#160;</td>
                  </tr>
                  <tr>
                    <td rowspan="1" style="width: 50.00%;">&#160;</td>
                    <td rowspan="1" style="width: 50.00%;">&#160;</td>
                  </tr>
                  <tr>
                    <td rowspan="1" style="width: 50.00%;">&#160;</td>
                    <td rowspan="1" style="width: 50%;">
                      <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[</font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;">VP of Corporate Development</font><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New
                            Roman&quot;;">]</font></font></div>
                    </td>
                  </tr>
                  <tr>
                    <td rowspan="1" style="width: 50.00%;">&#160;</td>
                    <td rowspan="1" style="width: 50.00%;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Vice President, Corporate Development</font></font></td>
                  </tr>
                  <tr>
                    <td rowspan="1" style="width: 50.00%;">&#160;</td>
                    <td rowspan="1" style="width: 50%;">
                      <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Biogen MA Inc.</font></font></div>
                    </td>
                  </tr>

              </table>
            </div>
            <div><br>
            </div>
            <div>
              <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">CONFIRMED ON BEHALF OF IONIS PHARMACEUTICALS, INC.:</font></div>
            </div>
            <div><br>
            </div>
            <table cellspacing="0" cellpadding="0" border="0" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="ze3a8729f5d404bb4b6aaf36792b768e7">

                <tr>
                  <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">By:</font></font></div>
                  </td>
                  <td style="width: 35%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
                </tr>
                <tr>
                  <td rowspan="1" style="width: 5%; vertical-align: top;">&#160;</td>
                  <td rowspan="1" style="width: 35%; vertical-align: top;">&#160;</td>
                  <td rowspan="1" style="width: 60%; vertical-align: top;">&#160;</td>
                </tr>
                <tr>
                  <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Name:</font></font></div>
                  </td>
                  <td style="width: 35%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
                </tr>
                <tr>
                  <td rowspan="1" style="width: 5%; vertical-align: top;">&#160;</td>
                  <td rowspan="1" style="width: 35%; vertical-align: top;">&#160;</td>
                  <td rowspan="1" style="width: 60%; vertical-align: top;">&#160;</td>
                </tr>
                <tr>
                  <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Title:</font></font></div>
                  </td>
                  <td style="width: 35%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
                </tr>
                <tr>
                  <td rowspan="1" style="width: 5%; vertical-align: top;">&#160;</td>
                  <td rowspan="1" style="width: 35%; vertical-align: top;">&#160;</td>
                  <td rowspan="1" style="width: 60%; vertical-align: top;">&#160;</td>
                </tr>
                <tr>
                  <td style="width: 5%; vertical-align: top; padding-bottom: 2px;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Date:</font></font></div>
                  </td>
                  <td style="width: 35%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</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;" id="z7e3a01a4456f4647a8be3ae413f9cba9">

                <tr>
                  <td style="width: 5%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Cc:</font></font></div>
                  </td>
                  <td style="width: 95%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Ionis Pharmaceuticals, Inc.</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 5%; vertical-align: top;">&#160;</td>
                  <td style="width: 95%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">2855 Gazelle Court</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 5%; vertical-align: top;">&#160;</td>
                  <td style="width: 95%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Carlsbad, CA 92010</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 5%; vertical-align: top;">&#160;</td>
                  <td style="width: 95%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Attention:&#160; General Counsel</font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 5%; vertical-align: top;">&#160;</td>
                  <td style="width: 95%; vertical-align: top;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">E-mail: [***]</font></div>
                  </td>
                </tr>

            </table>
            <div><br>
            </div>
            <div>
              <div style="text-align: center; font-family: &quot;Times New Roman&quot;; font-size: 10pt;">225 Binney Street, Cambridge, MA 02142 &#8226; Phone 781-464-2000 &#8226; www.biogen.com</div>
              <div style="text-align: center; font-family: &quot;Times New Roman&quot;; font-size: 10pt;"> <br>
              </div>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Exhibit A</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
                  </u></font></font></div>
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                  <td style="width: 28%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 52%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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                  <td style="width: 20%; vertical-align: top;">&#160;</td>
                  <td style="width: 28%; vertical-align: top;">&#160;</td>
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                      </font></div>
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                  <td style="width: 28%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 52%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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                  <td style="width: 20%; vertical-align: top;">&#160;</td>
                  <td style="width: 28%; vertical-align: top;">&#160;</td>
                  <td style="width: 52%; vertical-align: top;">&#160;</td>
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                  <td style="width: 28%; vertical-align: top;">&#160;</td>
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              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">184</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';"> <br>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">[</font><font style="font-size: 10pt; font-style: italic;">Date</font><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">]</font></font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Ionis Pharmaceuticals, Inc.</font></font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">2855 Gazelle Court</font></font></div>
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            <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Re:&#160; Establishment of Biogen-Approved Costs</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Dear [</font><font style="font-size: 10pt; font-family:
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            <div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="background-color: #FFFFFF; font-size: 10pt; font-family: 'Times New Roman';">Please indicate your concurrence with
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                  executing a copy of this letter and returning it to Biogen. This letter may be executed in counterparts, each of which will be deemed an original, notwithstanding variations in format or file designation which may result from electronic
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              <div style="text-align: center; font-family: &quot;Times New Roman&quot;; font-size: 10pt;">225 Binney Street, Cambridge, MA 02142 &#8226; Phone 781-464-2000 &#8226; www.biogen.com</div>
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              <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">CONFIRMED ON BEHALF OF IONIS PHARMACEUTICALS, INC.:</font></div>
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                  <td style="width: 35%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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                  <td rowspan="1" style="width: 5%; vertical-align: top;">&#160;</td>
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                  <td style="width: 35%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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                  <td rowspan="1" style="width: 5%; vertical-align: top;">&#160;</td>
                  <td rowspan="1" style="width: 35%; vertical-align: top;">&#160;</td>
                  <td rowspan="1" style="width: 60%; vertical-align: top;">&#160;</td>
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                  <td style="width: 35%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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                  <td rowspan="1" style="width: 5%; vertical-align: top;">&#160;</td>
                  <td rowspan="1" style="width: 35%; vertical-align: top;">&#160;</td>
                  <td rowspan="1" style="width: 60%; vertical-align: top;">&#160;</td>
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                  <td style="width: 35%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 60%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="background-color: rgb(255, 255, 255); font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Cc:</font></font></div>
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                  <td style="width: 5%; vertical-align: top;">&#160;</td>
                  <td style="width: 95%; vertical-align: top;">
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                  <td style="width: 95%; vertical-align: top;">
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                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">E-mail: [***]</font></div>
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              <div style="text-align: center; font-family: &quot;Times New Roman&quot;; font-size: 10pt;">225 Binney Street, Cambridge, MA 02142 &#8226; Phone 781-464-2000 &#8226; www.biogen.com</div>
              <div style="text-align: center; font-family: &quot;Times New Roman&quot;; font-size: 10pt;"> <br>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Exhibit A</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
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                  <td style="width: 28%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 52%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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                <tr>
                  <td style="width: 20%; vertical-align: top;">&#160;</td>
                  <td style="width: 28%; vertical-align: top;">&#160;</td>
                  <td style="width: 52%; vertical-align: top;">&#160;</td>
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                  <td style="width: 28%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td>
                  <td style="width: 52%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
                </tr>

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                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
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                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Biogen-Approved Costs</font></div>
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                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Apportionment of</font></div>
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                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">under Section 1.14.1(a)</font></div>
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                  <td style="width: 33%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 34%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 33%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 34%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 33%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                </tr>
                <tr>
                  <td style="width: 33%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 34%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 33%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                </tr>

            </table>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">187</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Schedule 1.1.4</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
                  </u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Biogen Conducted Non-ALS Targets</font></div>
            <div><br>
            </div>
            <div style="text-align: left;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z730f7022f76e457c9716a673ecde3854">

                    <tr>
                      <td style="width: 18pt;">&#160;</td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman';">1.</font></td>
                      <td style="vertical-align: top; text-align: left; width: auto;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <div style="text-align: left;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z680d815d66fc4fe6b485ef275746dd88">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: left;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <div style="text-align: left;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z668a4e3b22884a2d933d6ff19ed311f1">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: left;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <div style="text-align: left;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze512e0c9bcbb4ade9a1b2754ff005963">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: left;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <br>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">188</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Schedule 1.2.3(a)</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> <br>
                  </u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">ALS Targets</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: left;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfd4c5d8dcfa04e248e01ded621dc2334">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">1.</font></td>
                      <td style="vertical-align: top; text-align: left;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">SOD-1</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <div style="text-align: left;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zae7df2b7c06749bcae9b048f031e2de5">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman';">2.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: left;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <div style="text-align: left;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7f615e82afce4b23989a4994c94a578a">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">3.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: left;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <div style="text-align: left;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z74d4d8c8121249829397aec43ef39931">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">4.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: left;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <div style="text-align: left;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2e3be5645d3c4879ad3b39561c74b17b">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">5.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: left;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                      </td>
                    </tr>

                </table>
                <div> <br>
                </div>
              </div>
            </div>
            <div style="text-align: left;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf74f911a305e4bfd87ffd07a86f18302">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">6.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: left;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">189</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Schedule 1.2.4</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Terms and Conditions for Provision of Research ASOs to Biogen</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">ARTICLE<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"> 1</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">DEFINITIONS</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">The terms used in this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font> with
                initial letters capitalized, whether used in the singular or the plural, will have the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Attachment 1</u></font>, or if not
                listed in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Attachment 1</u></font>, the meaning designated in places throughout the Agreement (or <font style="font-size: 10pt; font-family: 'Times
                  New Roman'; font-variant: small-caps;"><u>Appendix 1</u></font> to the Agreement).</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE<font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"> 2</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">PROVISION OF RESEARCH ASOS OUTSIDE OF THE DISEASE RESEARCH PROGRAM</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">2.1. Scope of Collaboration.</font></div>
            <div><br>
            </div>
            <div>
              <div>
                <div>
                  <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z7a02100157f04288a28f6b8e892c96dd" style="width: 100%; font-family: 'Times New Roman'; font-size: 10pt;">

                      <tr style="vertical-align: top;">
                        <td style="width: 18pt;">&#160;</td>
                        <td style="vertical-align: top; width: 18pt;">
                          <div style="text-align: justify;"><font style="text-align: left; font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">a)</font></div>
                        </td>
                        <td style="align: left; vertical-align: top; width: auto;">
                          <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will generate Research ASOs for Accepted Gene Targets in accordance with the terms and conditions of this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font>.</font></div>
                        </td>
                      </tr>

                  </table>
                </div>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z2a7f8d5605ef411b9e723bff92a3f541">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Each Party will devote commercially reasonable efforts to performing its obligations under the Target Validation Plan.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE<font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"> 3</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">CONDUCT OF THE TARGET VALIDATION OUTSIDE OF THE DISEASE RESEARCH PROGRAM</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.1. Selection of Biogen TV Targets; Target Validation Activities.</font></div>
            <br>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4e9242ef2a94473aa37ad2e354abc31e">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">During the Research Term, Biogen will have the right to propose gene targets that are the focus of Biogen programs that are not part of the Collaboration (each, a &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen TV Target</font>&#8221;) for up to a total of [***] Accepted Gene Targets per [***] period. Biogen will propose such Biogen TV
                            Targets by written notice to the Ionis Alliance Manager.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z942c5ffb9a0244059aea41ecb4767c82">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis may reject a proposed Biogen TV Target if, at the time of such proposal, [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6fa4f8e3c767475f81f88d9ae7c96bff">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Each Biogen TV Target that is not rejected by Ionis will be an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style:
                              italic;">Accepted Gene Target.</font>&#8221; During the Research Term, Ionis and Biogen will use Commercially Reasonable Efforts to perform the activities outlined in the Target Validation Plan on each Accepted Gene Target.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">190</font></div>
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            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.2. Biogen&#8217;s Use of Research ASOs and Information.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3f33991d2f7248fb87e43663ce0af8e1">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Research ASOs and any related Confidential Information provided to Biogen by Ionis hereunder are proprietary to Ionis.&#160; Biogen will not distribute or release
                            the Research ASOs to any Person other than its employees, academic collaborators, Affiliates, agents or (sub)contractors, solely for purposes of performing work in support of Biogen&#8217;s drug discovery activities. Subject to the
                            terms and conditions of this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font>, Ionis hereby grants Biogen a non-exclusive, fully paid, license to use the
                            Ionis Confidential Information (including data generated by Ionis with Research ASOs in the performance of the Target Validation Plan) and Research ASOs solely for use in support of Biogen' drug discovery purposes. In exercising
                            its rights under this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font>, Biogen may use data generated by Biogen using the Research ASOs (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Data</font>&#8221;) to support Patent Rights filed by or on behalf of Biogen, including Patent Rights that claim methods of
                            treating disease by modulating the applicable Accepted Gene Target. The claims of any such Biogen Patent Right using such Biogen Data that generically claims methods of treating disease by modulating the applicable Accepted Gene
                            Target, but are not directed to specific compounds or agents, are referred to as the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Licensed Claims</font>.&#8221;
                            Notwithstanding the foregoing, Biogen will not use such Biogen Data to support claims directed to one or more Oligonucleotides as a composition of matter or one or more Oligonucleotides as a pharmaceutical product, without the
                            prior written consent of Ionis. In addition, Biogen may not use Ionis data disclosed to Biogen in connection with this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font>
                            or the Research ASOs to make products that incorporate Oligonucleotides.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3e1f46e289fe4466a7aecb167e18ae75">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Biogen hereby grants Ionis a non-exclusive, fully-paid sublicensable license under any Biogen Licensed Claims solely for the purpose of discovering, developing or
                            commercializing an Oligonucleotide(s) as a pharmaceutical product, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that such license will only be sublicensable by
                            Ionis to a Third Party licensee in connection with the grant of an exclusive license to such Third Party under other Ionis intellectual property with respect to such Oligonucleotide. No other license is granted to Ionis under
                            any Biogen-owned or controlled Patent Right or other intellectual property under this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font>.&#160; For avoidance of
                            doubt, no rights are granted by Biogen to Ionis under this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font> (expressly or by implication or otherwise) with
                            respect to any compounds, materials or agents (or any method of use or manufacture thereof).</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zcce5f45dd6dc472db1e425892c9e8bd7">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis hereby grants Biogen a non-exclusive, fully-paid sublicensable license under any Ionis Licensed Claims solely for the purpose of discovering, developing or
                            commercializing a non-Oligonucleotide compound(s) as a pharmaceutical product, <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that such license will only be
                            sublicensable by Biogen to a Third Party licensee in connection with the grant of an exclusive license to such Third Party under other Biogen intellectual property with respect to any such non&#8209;Oligonucleotide compound. &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Licensed Claims</font>&#8221; means the claims of any Ionis Invention that generically claims methods of treating disease by
                            modulating an Accepted Gene Target, but are not directed to any specific compound or agent (including any Oligonucleotide).&#160; Except as set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                                3.2(a)</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>(c)</u></font>, no other license is granted to Biogen under any Ionis-owned or controlled Patent Right or other intellectual property
                            under this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.3. Non-exclusive Collaboration.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z10b8c70862954f63a037f4766cf96ae2">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis will perform target validation activities and will provide Research ASOs to Biogen as set forth in the Target Validation Plan on a non-exclusive basis. Ionis
                            may collaborate with Third Parties for target validation studies on any gene targets, including Accepted Gene Targets. In addition, this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule












                                1.2.4</u></font> will not limit Ionis from conducting research, discovery and development work on any and all Oligonucleotides, for itself or with or on behalf of a Third Party.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z39180b2518fe4aae99d7d28a05f9b84b">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If an Oligonucleotide to an Accepted Gene Target hereunder becomes a drug development candidate of Ionis or a Third Party collaborator of Ionis, Ionis will notify
                            Biogen. Upon receipt of such notice from Ionis, Biogen will return to Ionis all unused quantities of applicable TV Compound within [***] days after the date on which Biogen received such notice.&#160; After such time, Ionis will not
                            have any obligation to provide additional quantities of the originally supplied TV Compound to Biogen under this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">191</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="ze2aa2c3b0f7844289db9d661c309b55c">

                    <tr>
                      <td style="width: 18pt;">&#160;</td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">c)</font></td>
                      <td style="vertical-align: top; text-align: justify; width: auto;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">If Ionis achieves Target Sanction for an Accepted Gene Target, and Ionis does not at such time have any obligations to any Third Party with respect to such Accepted
                            Gene Target that would conflict with Ionis&#8217; compliance with this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.3(c)</u></font>, Ionis will provide to Biogen a Target Sanction Data Package for such
                            Accepted Gene Target (an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">AGT Target Sanction Data Package</font>&#8221;) and Biogen will have [***] days following receipt of such
                            AGT Target Sanction Data Package to decide whether to negotiate with Ionis regarding an agreement with respect to such Accepted Gene Target (an &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;
                              font-style: italic;">AGT Agreement</font>&#8221;).&#160; Following delivery of an AGT Target Sanction Data Package, Ionis will not initiate negotiations regarding or enter into an AGT Agreement with any Third Party until the earlier to
                            occur of: (1) Biogen notifying Ionis that it declines the opportunity to negotiate with Ionis regarding such AGT Agreement; (2) Biogen not responding to Ionis within [***] days after receipt of such AGT Target Sanction Data
                            Package; or (3) the AGT Negotiation Period expiring before Biogen and Ionis have entered into such AGT Agreement.&#160; If Biogen or one of its Affiliates responds within 30 days after its receipt of the AGT Target Sanction Data
                            Package indicating that Biogen or one of its Affiliates desires to negotiate with Ionis regarding the proposed AGT Agreement, Ionis and Biogen or one of its Affiliates will negotiate in good faith for 180 days thereafter (or
                            such other period as mutually agreed by the Parties) (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">AGT</font>&#160;<font style="font-size: 10pt; font-family: 'Times New
                              Roman'; font-weight: bold; font-style: italic;">Negotiation Period</font>&#8221;) regarding a mutually satisfactory AGT Agreement. During the AGT Negotiation Period, Biogen or its Affiliate will make the first written proposal to
                            Ionis setting forth all material business and legal terms on which Biogen or its Affiliate would be willing to enter into the proposed AGT Agreement with Ionis; <font style="font-size: 10pt; font-family: 'Times New Roman';
                              font-style: italic;">provided </font>that neither Party will have any obligation to enter into an AGT Agreement. If the AGT Negotiation Period expires before Biogen or its Affiliate and Ionis have entered into such AGT
                            Agreement, Ionis will have no further obligation to negotiate with Biogen or its Affiliates with respect to such AGT Agreement and Ionis will be free to negotiate and enter an agreement with a Third Party with respect to an AGT
                            Agreement [***]; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided, however</font>, that Ionis will not enter into any such AGT Agreement with any Third Party unless the terms and
                            pricing of such AGT Agreement, [***].</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">3.4. Biogen Materials.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Any materials provided by Biogen to Ionis in connection with a Biogen TV Target or Accepted Gene Target, including any biological materials with
                respect to screening assays, including any progeny, expression products, mutants, replicates, derivatives and modifications thereof, (such materials being individually and collectively referred to as the &#8220;<font style="font-size: 10pt;
                  font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Materials</font>&#8221;) will be used by Ionis solely for purposes of performing activities in accordance with the&#160; Target Validation Plan and any remaining Biogen
                Materials will be returned to Biogen (or destroyed as may be requested by Biogen in writing) promptly following the end of the applicable activities under the Target Validation Plan or earlier upon request by Biogen. All information related
                to such Biogen Materials will be Biogen Confidential Information. All such materials must be used with prudence and appropriate caution in any experimental work, since all of their characteristics may not be known.</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">ARTICLE<font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"> 4</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;">INTELLECTUAL PROPERTY</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.1. Ownership of Inventions.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z046e896c2f054f109a51368c9be4f2b9">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Title to any inventions, technology, discoveries, or other proprietary property made or discovered (as determined by the U.S. laws of inventorship) by employees of
                            or consultants or contractors of a Party pursuant to the performance Target Validation Plan (collectively, &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Inventions</font>&#8221;)







                            are retained by the Party that is the employer of the inventor (or, in the case of consultants or contractors, the Party for which such consultant or contractor is providing services). Ionis will own Inventions invented solely
                            by employees or consultants or contractors of Ionis and any Patent Rights claiming such Invention (collectively, the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis
                              Inventions</font>&#8221;). Biogen will own Inventions invented solely by employees or consultants or contractors of Biogen and any Patent Rights claiming such Invention.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">192</font></div>
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            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc93705a3102c4196a1ea80458545132c">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Except as provided otherwise herein, Ionis and Biogen will jointly hold title to all Inventions, made or discovered (as determined by the U.S. laws of inventorship)
                            jointly by employees or consultants or contractors of Ionis and Biogen (&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Joint Inventions</font>&#8221;). Patent Rights claiming
                            such Joint Inventions will be &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Joint Patents.</font>&#8221;&#160; Ionis and Biogen will promptly provide each other with notice whenever
                            a Joint Invention is made or discovered.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z8086db0105a24860a0970d11d0fba2d1">

                    <tr>
                      <td style="width: 18pt;"><br>
                      </td>
                      <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Parties agree, upon reasonable request, to execute any documents reasonably necessary to effect and perfect each other&#8217;s ownership of any Invention or Patent
                            Right claiming such Invention.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">4.2. Patent Prosecution; Infringement of Joint Patents.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z83ca160b5bfc424a97313f79cb988614">

                    <tr>
                      <td style="width: 13.5pt;"><br>
                      </td>
                      <td style="width: 22.5pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Each Party has the right to file, prosecute, maintain, enforce and defend Patent Rights on Inventions owned by such Party, at its own expense.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfc47320e92fc4657b58a21fb97d69d22">

                    <tr>
                      <td style="width: 13.5pt;"><br>
                      </td>
                      <td style="width: 22.5pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ionis and Biogen will mutually agree on the filing, prosecution and maintenance of any Joint Patents and the expenses of such prosecution and maintenance will be
                            shared equally. If either Party elects not to participate in the filing, prosecution or maintenance of a Joint Patent, it will notify the other Party of such election not later than [***] days before the applicable deadline for
                            filing, prosecution or maintenance, and the other Party will thereafter have the right to undertake such filing, prosecution or maintenance, at its own expense.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7c28d2489128432aa721729d0a8fd535">

                    <tr>
                      <td style="width: 13.5pt;"><br>
                      </td>
                      <td style="width: 22.5pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">A Party whose rights in a Joint Patent are impacted by the infringement of such Joint Patent by a Third Party will have the right to enforce that Joint Patent at
                            its own discretion and at its own expense. The non-enforcing Party agrees to provide the enforcing Party all reasonable assistance (including joining such action as a Party plaintiff), at the enforcing Party&#8217;s expense. Any
                            damages or other recovery, whether by settlement or otherwise, from an action hereunder to enforce a Joint Patent will be paid first to each Party to reimburse the costs of enforcement and then prorated to the Party(ies) based
                            on damages incurred.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ARTICLE<font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"> 5</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">TERM AND TERMINATION</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.1. Agreement Term.</font></div>
            <div><br>
            </div>
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Unless the Agreement is earlier terminated (in which case this <font style="font-size: 10pt; font-family: 'Times New Roman';
                  font-variant: small-caps;"><u>Schedule 1.2.4</u></font> will also terminate), this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font> will remain in effect until the end
                of the Research Term (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Term</font>&#8221;), at which time it will expire.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">5.2. Survival.</font></div>
            <div><br>
            </div>
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2</u></font> (Biogen&#8217;s Use of Research ASOs and
                Information), <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.2</u></font> (Survival) and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>ARTICLE 4</u></font> (Intellectual Property) will
                survive the expiration or termination of this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule 1.2.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">193</font></div>
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            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Attachment 1 </u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>to</u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u> Schedule </u></font><font style="font-size: 10pt;
                  font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>1.2.4</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Definitions</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Accepted Gene Target</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">AGT Agreement</font>&#8221; has the meaning set forth
                in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.3(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">AGT Negotiation Period</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.3(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">AGT Target Sanction Data Package</font>&#8221; has
                the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.3(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Data</font>&#8221; has the meaning set forth
                in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Licensed Claims</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen Materials</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.4</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Biogen TV Target</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.1(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Inventions</font>&#8221; has the meaning set forth in
                <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Inventions</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1(a)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Ionis Licensed Claims</font>&#8221; has the meaning
                set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 3.2(c)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Joint Invention</font>&#8221; has the meaning set
                forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Joint Patents</font>&#8221; has the meaning set forth
                in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 4.1(b)</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Target Validation Plan</font>&#8221; means the
                collaborative Target Validation Plan undertaken by the Parties pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family:
                  'Times New Roman'; font-variant: small-caps;"><u>1.2.4</u></font>, as further described in <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Attachment</u></font><font style="font-size: 10pt;
                  font-family: 'Times New Roman';"><u> 2</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Term</font>&#8221; has the meaning set forth in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 5.1</u></font>.</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">TV Compound</font>&#8221; means an Oligonucleotide
                delivered to Biogen by Ionis under this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant:
                  small-caps;"><u>1.2.4 </u></font>directed to an Accepted Gene Target.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">194</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Attachment 2</u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> to</u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u> Schedule 1.2.4</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Target Validation Plan</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">195</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> 1.6.1</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">ALS Letter Agreement</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">196</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> 1.10.2(c)</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Ionis&#8217; Standard IND-Enabling Toxicology Studies</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">197</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>1.10.2(d)</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Initial Development Plan Requirements</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">198</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>1.10.2(d)(v)</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Study Synopsis Requirements</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">199</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>1.10.2(e)</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Apportionment of Certain Milestone Payments and Biogen-Approved Costs</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">In the event that either (I) a milestone payment established under <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                    1.10.2(e)</u></font> or (II) Biogen-Approved Costs resulting from [***], such milestone payment or Biogen-Approved Costs, as applicable, shall be apportioned into smaller milestone payments and paid by Biogen to Ionis as follows:</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***].</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Each payment due under this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>1.10.2(e)</u></font> shall be payable by Biogen within [***] days after receipt of the applicable invoice by Biogen following the event that triggered such milestone payment.</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">200</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Schedule 1.10.6</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Ionis API Supply for ALS Collaboration Programs and Biogen Conducted Non-ALS Collaboration Programs</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">201</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Schedule 1.18.1</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Collaboration Steering Committee Governance</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>CSC Representatives</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Ionis</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Lynne Parshall, Senior Strategic Advisor</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Frank Bennett, SVP, Head of Research</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Richard Geary, SVP, Head of Development</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;"><u>Biogen</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Michael Ehlers, EVP, Research and Development</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Katherine Dawson, VP, Late Stage Clinical Development</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Anabella Villalobos, SVP, Biotherapeutic and Medicinal Sciences</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Daniel Karp, EVP Corporate Development</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">202</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Schedule 1.18.2</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Neurology JRC Governance</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z7484023f8b09411195f60c3b7edf470b">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Neurology JRC will determine the Neurology JRC operating procedures, including frequency of meetings (at least quarterly), location of meetings, and
                            responsibilities for agendas and minutes. The Neurology JRC will codify these operating procedures in the written minutes of the first meeting.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc55994bec9794e87a43902c64b975dee">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Neurology JRC may hold meetings in person or by audio or video conference as determined by the Neurology JRC; but at least two meetings per year will be in
                            person (one held at Ionis&#8217; facilities, and the other held at Biogen&#8217;s facilities in the U.S.). Alliance Managers will attend Neurology JRC meetings as participating non-members. In addition, upon prior approval of the other
                            Party, each Party may invite its employees or consultants to attend Neurology JRC meetings, including any subject matter expert(s) with valuable knowledge of High Interest Targets or Collaboration Targets (as applicable) or the
                            diseases associated with such targets.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z02d8c5a890bf454e96202e93cf8ac296">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The co-chairs will be responsible for ensuring that activities occur as set forth in this Agreement, including ensuring that Neurology JRC meetings occur, Neurology
                            JRC recommendations are properly reflected in the minutes, and any dispute is given prompt attention and resolved in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.2</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.3</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font>, as applicable.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z049033c8a01f4a098f2bce71101b1e66">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Neurology JRC members from the same Party will collectively have one vote. The Neurology JRC will strive to make recommendations with approval of both Ionis
                            members and Biogen members, and record such recommendations in the minutes of the applicable Neurology JRC meeting.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z6086eeacb6b2483982db466c44ff4e9f">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;">
                        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(</font><font style="font-weight: bold;">e<font style="font-size:
                              10pt; font-family: &quot;Times New Roman&quot;;">)</font></font></div>
                      </td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Neurology JRC 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 Neurology JRC dissolves.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">203</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Schedule 1.18.3</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Neurology JDC Governance</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfd33f5c4439e486ab8acea14eae7a20f">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Neurology JDC will determine its operating procedures, including frequency of meetings (at least quarterly), location of meetings, and responsibilities for
                            agendas and minutes. The Neurology JDC will codify these operating procedures in the written minutes of its first meeting.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z0a5682f151b14de8b57a886136db3ba7">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Neurology JDC may hold meetings in person or by audio or video conference as determined by the Neurology JDC; but at least two meetings per year will be in
                            person (one held at Ionis&#8217; facilities, and the other held at Biogen&#8217;s facilities in the U.S.). Alliance Managers will attend Neurology JDC meetings as participating non-members. In addition, upon prior approval of the other
                            Party, each Party may invite its employees or consultants to attend Neurology JDC meetings, including any subject matter expert(s) with valuable knowledge of the applicable or Collaboration Target or the diseases associated with
                            such target.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zc3b1af152d654e3c905f18ba5f366f44">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The co-chairs will be responsible for ensuring that activities occur as set forth in this Agreement, including ensuring that Neurology JDC meetings occur, Neurology
                            JDC recommendations are properly reflected in the minutes, and any dispute is given prompt attention and resolved in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.18.3</u></font>, <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 7.1.3</u></font> and <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1</u></font>, as applicable.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zf2d63c52cde942cfb144d8c91f6c8df9">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Neurology JDC members from the same Party will collectively have one vote. The Neurology JDC will strive to make recommendations with approval of both Ionis members
                            and Biogen members, and record such recommendations in the minutes of the applicable Neurology JDC meeting.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z4747d6dbe5f84c3387199eb917711024">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;">
                        <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(</font><font style="font-weight: bold;">e<font style="font-size:
                              10pt; font-family: &quot;Times New Roman&quot;;">)</font></font></div>
                      </td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">The Neurology JDC 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 Neurology JDC dissolves.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">204</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Schedule 1.18.6</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Alliance Management Activities</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Each Alliance Manager is responsible for:</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z84becb602231441a9cbe1f3541a34d38">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(a)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Promoting the overall health of the relationship between the Parties;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb7351996b72146baacf1269bd9f494ee">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(b)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Developing a mutually agreed alliance launch plan covering any activities and systems that the Parties need to implement within the first 100 days after the
                            Effective Date to support the Collaboration;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zace5e5728d02418c83f7d948665299d0">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(c)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Organizing CSC, Neurology JRC and Neurology JDC meetings, including agendas, drafting minutes, and publishing final minutes;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z3d8b459f11c54d019a41b5f877bb819e">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(d)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Supporting the co-chairs of the CSC, Neurology JRC and Neurology JDC with organization of meetings, information exchange, meeting minutes, and facilitating dispute
                            resolution as necessary;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zb792dcca6b4e4789a0453925fe572a3c">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(e)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Preparing status and progress reports on the above as determined necessary by the CSC, Neurology JRC and Neurology JDC;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="za71243f1cc454e0e9add70ef35881314">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(f)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ensuring compliance in maintaining the Ionis Internal ASO Safety Database as outlined in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section
                                5.2</u></font>;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z1fc3ab82fe7c427c90bad030f013e8e5">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(g)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Manage and coordinate the target validation activities under <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule
                                1.2.4</u></font>;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zfeae874e31f84010a67d98de73816685">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(h)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Ensuring proper approval of publications prior to submission as required in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 11.4</u></font>;</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="z9d970a8a60e94174b12d2535adecc16e">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(i)</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';">Determining an appropriate format for summaries of resource and FTE utilization, and ensuring such summarized are timely provided to the Neurology JRC as outlined
                            in <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.11</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">205</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
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            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>4.3.1(a)</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Drug Substance Process and Formulation Development Activities</font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-style: italic;">[***]</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">206</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>4.8.2(c)</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Ionis&#8217; Fully Absorbed Cost of Goods Methodology</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Cost Estimate of API Cost per Kilogram</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">(OOO&#8217;s)</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">207</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>5.1.4</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u> <br>
                  </u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Biogen&#8217;s Development and Commercialization Activities</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-style: italic;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>[***]</u></font></font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">208</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Schedule 5.1.6</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Integrated Development Plan Content</font></div>
            <div><br>
            </div>
            <table cellspacing="0" cellpadding="0" border="0" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="z2ce5da7b198b4854a9686bb94e471824">

                <tr>
                  <td style="width: 15%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
                  </td>
                  <td colspan="2" style="vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
                  </td>
                  <td colspan="2" style="vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
                  </td>
                  <td colspan="2" style="vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="background-color: rgb(255, 255, 255); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); vertical-align: top; width: 15%;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="background-color: #FFFFFF; border-bottom: 2px solid #000000; border-left: #000000; border-top: 2px solid #000000; vertical-align: top; width: 3%;"> <br>
                  </td>
                  <td style="width: 25%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);"><br>
                  </td>
                  <td style="width: 25%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);"> <br>
                  </td>
                  <td style="width: 26%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="background-color: rgb(204, 238, 255); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); vertical-align: top; width: 15%;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
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                  <td style="width: 25%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div>&#160;&#160;&#160;&#160;&#160;&#160;&#160; <br>
                    </div>
                  </td>
                  <td style="width: 25%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td rowspan="3" style="width: 3%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td rowspan="3" style="width: 26%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                </tr>
                <tr>
                  <td style="background-color: rgb(255, 255, 255); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); vertical-align: top; width: 15%;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="background-color: #FFFFFF; border-bottom: 2px solid #000000; border-left: #000000; border-top: 2px solid #000000; vertical-align: top; width: 3%;"> <br>
                  </td>
                  <td style="width: 25%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
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                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="background-color: #CCEEFF; border-bottom: 2px solid #000000; border-left: 2px solid #000000; border-right: #000000; border-top: 2px solid #000000; vertical-align: top; width: 15%;">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);"> <br>
                  </td>
                  <td style="width: 25%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
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                    </div>
                  </td>
                  <td style="width: 25%; vertical-align: top; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>

            </table>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">209</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>6.10.2(e)</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Royalty Calculation Examples</font></div>
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            <table cellspacing="0" cellpadding="0" border="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse;" id="zb678d96c72ca41a4a0a8a4d637a51515">

                <tr>
                  <td style="width: 10.77%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 10.63%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 10.07%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 12.04%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 12.04%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 12.04%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 11.09%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 11.09%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 10.24%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 10.77%; vertical-align: top; background-color: rgb(255, 255, 255); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 10.77%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 10.24%; vertical-align: middle; background-color: rgb(255, 255, 255); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
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                  <td style="width: 10.63%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 10.07%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 12.04%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 12.04%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 12.04%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 11.09%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 11.09%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 10.24%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>

            </table>
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
              </font></div>
            <div style="text-align: left; margin-left: 18pt;"> <font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse;" id="z5b7de15f8fd845a0b3850852a7f0162c">

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            <div style="text-align: left; margin-left: 18pt;"> <font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
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                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
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                  <td style="width: 11.09%; vertical-align: middle; background-color: rgb(255, 255, 255); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 11.09%; vertical-align: middle; background-color: rgb(255, 255, 255); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 10.24%; vertical-align: middle; background-color: rgb(255, 255, 255); border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 10.77%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 10.63%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 10.07%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 12.04%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 12.04%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 12.04%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 11.09%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 11.09%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 10.24%; vertical-align: top; border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>

            </table>
            <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><sup style="vertical-align: text-top; line-height: 1; font-size: smaller;"> <br>
                </sup></font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">210</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>6.10.2(f)</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
                  </u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Allocation of Net Sales</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">211</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 6.13.1</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
                  </u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Certain Ionis In-License Agreements</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">(Relevant to the High Interest Targets as of the Effective Date)</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;">[***]</font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">212</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule </u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 8.2.4(a)</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
                  </u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Ionis Core Technology Patents</font></div>
            <div><br>
            </div>
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                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>[***]</u></font></font></div>
                  </td>
                  <td style="width: 16.45%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>[***]</u></font></font></div>
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                  <td style="width: 17.96%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>[***]</u></font></font></div>
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                  <td style="width: 26%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>[***]</u></font></font></div>
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                  <td style="width: 14.17%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>[***]</u></font></font></div>
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                  <td style="width: 15.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.45%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 17.96%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 26%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 14.17%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                </tr>
                <tr>
                  <td style="width: 9.74%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 15.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 16.45%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 17.96%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 26%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 14.17%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 9.74%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 15.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.45%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 17.96%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 26%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 14.17%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                <tr>
                  <td style="width: 9.74%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 15.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.45%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 17.96%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 26%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 14.17%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
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                  <td style="width: 15.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 16.45%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
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                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 14.17%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                </tr>
                <tr>
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                  <td style="width: 15.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.45%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 17.96%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
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                  <td style="width: 26%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 14.17%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 15.67%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0) rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 16.45%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
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            </table>
            <div> <br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">213</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 8.2.4(b)</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Ionis Manufacturing and Analytical Patents</font></div>
            <div><br>
            </div>
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                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 22%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 11.53%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 17.47%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 17.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.56%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 14.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 22%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 11.53%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 17.47%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 17.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.56%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 14.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 22%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 11.53%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 17.47%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 17.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.56%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 14.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 22%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 11.53%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 17.47%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 17.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.56%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 14.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 22%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 11.53%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 17.47%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 17.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.56%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 14.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 22%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 11.53%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 17.47%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">&#160;</td>
                  <td style="width: 17.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.56%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 14.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 22%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 11.53%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 17.47%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 17.05%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 16.56%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 14.83%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 22%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 11.53%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                </tr>

            </table>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div id="DSPFPageNumberArea" style="text-align: center;"><font id="DSPFPageNumber" style="font-family: &quot;Times New Roman&quot;; font-size: 8pt; font-weight: normal; font-style: normal;">214</font></div>
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 8.2.4(c)</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
                  </u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Ionis Product-Specific Patents</font></div>
            <div><br>
            </div>
            <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse;" id="zd0492a63f053433da4275392e0a49ff2">

                <tr>
                  <td style="width: 13.94%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>[***]</u></font></font></div>
                  </td>
                  <td style="width: 17.72%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>[***]</u></font></font></div>
                  </td>
                  <td style="width: 18.61%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>[***]</u></font></font></div>
                  </td>
                  <td style="width: 20.32%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>[***]</u></font></font></div>
                  </td>
                  <td style="width: 29.41%; vertical-align: middle; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>[***]</u></font></font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 13.94%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 17.72%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 18.61%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 20.32%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                  <td style="width: 29.41%; vertical-align: middle; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">&#160;</td>
                </tr>

            </table>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Schedule 8.2.8</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
                  </u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Prior Agreements</font></div>
            <div><br>
            </div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
            <div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman';"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 10.4.5(b)</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center; text-indent: -36pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Advisory Panel Regarding Setoff Disputes</font></div>
            <div style="text-align: center; text-indent: -36pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>[***]</u></font></font></div>
            <div><br>
            </div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Schedule 10.4.6</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Transition Services</font></div>
            <div><br>
            </div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"> <br>
              </font></div>
            <div style="clear: both; margin-top: 10pt; margin-bottom: 10pt;" id="DSPFPageBreakArea">
              <div style="page-break-after:always;" id="DSPFPageBreak">
                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Schedule 12.1.2</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Mediation</font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"> <br>
              </font></div>
            <div style="text-align: justify;">
              <div>
                <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%;" class="DSPFListTable" id="zdf2bbba7f673464daa5d09b6b75e99f2">

                    <tr>
                      <td style="width: 36pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.</font></td>
                      <td style="width: auto; vertical-align: top; text-align: justify;">
                        <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Mediation</u></font>.</font></div>
                      </td>
                    </tr>

                </table>
              </div>
            </div>
            <div><br>
            </div>
            <div style="text-align: justify; text-indent: 36pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.1.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160;&#160; <font style="font-size: 10pt; font-family: 'Times New Roman';">If a
                Dispute cannot be resolved pursuant to <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 12.1.1</u></font> of the Agreement (Escalation), the Parties agree to try in good faith to resolve any such Dispute by
                non-binding mediation administered by the American Arbitration Association (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">AAA</font>&#8221;) in accordance with its Commercial Mediation
                Procedures then in effect (the &#8220;<font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-style: italic;">Procedures</font>&#8221;), as modified by this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section











                    1.1</u></font> of this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant: small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.1.2</u></font>.&#160; The mediation
                will be conducted by a single mediator appointed by agreement of the Parties, within 15 days after either Party notifies the other Party of its intention to mediate such Dispute, or failing such agreement, appointed by the AAA in accordance
                with the Procedures; <font style="font-size: 10pt; font-family: 'Times New Roman'; font-style: italic;">provided</font>, that in either case the mediator will be a retired Delaware state or federal judge.&#160; Unless otherwise mutually agreed
                upon by the Parties, the mediation proceedings will be conducted in Dover, Delaware. The Parties agree that they will share equally the costs and expenses of the mediation; <font style="font-size: 10pt; font-family: 'Times New Roman';
                  font-style: italic;">provided</font>, that each Party will bear its own attorneys&#8217; fees and associated costs and expenses.&#160; The mediation conference will be held within [***] days after appointment of the mediator, and will last no more
                than two consecutive days unless otherwise mutually agreed upon by the Parties.&#160; Any resolution of a Dispute by mediation pursuant to this <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.1</u></font> of these
                mediation procedures will be in writing and signed by duly authorized representatives of both Parties.</font></div>
            <div><br>
            </div>
            <div style="text-align: justify; text-indent: 36pt; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">1.2.</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160; &#160; &#160;&#160; <font style="font-size: 10pt; font-family: 'Times New Roman';">If
                the Parties cannot resolve a Dispute in accordance with <font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Section 1.1</u></font> of this <font style="font-size: 10pt; font-family: 'Times New Roman'; font-variant:
                  small-caps;"><u>Schedule</u></font><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> 12.1.2</u></font>, then such Dispute will be resolved by the Parties in accordance with <font style="font-size: 10pt; font-family:
                  'Times New Roman';"><u>Section 12.2</u></font> of the Agreement (Governing Law; Jurisdiction; Venue; Service of Process).</font></div>
            <div><br>
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            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>Schedule 12.5</u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u> <br>
                  </u></font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';">T</font><font style="font-size: 10pt; font-family: 'Times New
                  Roman'; font-variant: small-caps;">able</font><font style="font-size: 10pt; font-family: 'Times New Roman';"> A</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Applicable License Fee Payments in Change of Control for Collaboration Products</font></div>
            <div><br>
            </div>
            <table cellspacing="0" cellpadding="0" border="0" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="z2ab47baba6944cb39992e2e0d5cd736e">

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                  <td style="width: 60%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>[***]</u></font></font></div>
                  </td>
                  <td style="width: 20%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>[***]</u></font></font></div>
                  </td>
                  <td style="width: 20.1%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><u>[***]</u></font></font></div>
                  </td>
                </tr>
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                  <td style="width: 60%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 20%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 20.1%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 60%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 20%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 20.1%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 60%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 20%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 20.1%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 60%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 20%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 20.1%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 60%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 20%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 20.1%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>

            </table>
            <div><br>
            </div>
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                <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold; font-variant: small-caps;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><u>Schedule 12.5</u></font></font></div>
            <div><br>
            </div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">T</font><font style="font-size: 10pt;
                  font-family: &quot;Times New Roman&quot;; font-variant: small-caps;">able</font><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"> B</font></font></div>
            <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Applicable [***] under Section 12.5.1(b) in Change of Control</font></div>
            <div><br>
            </div>
            <table cellspacing="0" cellpadding="0" border="0" style="font-family: &quot;Times New Roman&quot;; font-size: 10pt; width: 100%; border-collapse: collapse;" id="zcd310832d1c248e58ba165c0f1d195ed">

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                  <td style="width: 24.05%; vertical-align: bottom; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 3.79%; vertical-align: bottom;">&#160;</td>
                  <td style="width: 24.05%; vertical-align: bottom; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-top: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3.79%; vertical-align: bottom;">&#160;</td>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3.79%; vertical-align: bottom;">&#160;</td>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3.79%; vertical-align: bottom;">&#160;</td>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3.79%; vertical-align: bottom;">&#160;</td>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3.79%; vertical-align: bottom;">&#160;</td>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
                  </td>
                  <td style="width: 3.79%; vertical-align: bottom;">&#160;</td>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(204, 238, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                </tr>
                <tr>
                  <td style="width: 24.05%; vertical-align: bottom; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman';">[***]</font></div>
                  </td>
                  <td style="width: 24.05%; vertical-align: bottom; border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);">
                    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">[***]</font></div>
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                  <td style="width: 3.79%; vertical-align: bottom;">&#160;</td>
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<DOCUMENT>
<TYPE>EX-10.69
<SEQUENCE>4
<FILENAME>exhibit10_69.htm
<DESCRIPTION>EXHIBIT 10.69
<TEXT>
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      <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Final Execution Version</div>
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    <div style="text-align: right;"><font style="font-weight: bold; font-family: 'Times New Roman'; font-size: 10pt;"><u>Exhibit 10.69</u></font></div>
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    <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">CONFIDENTIAL TREATMENT REQUESTED</font></div>
    <div style="text-align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">UNDER 17 C.F.R. &#167;&#167; 200.80(b)(4), 240.24B-2</font></div>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">AMENDMENT NO. 1</font></div>
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    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">This Amendment No. 1 (the &#8220;Amendment&#8221;) to the Strategic Collaboration Agreement dated July 31<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">st</sup>, 2015 (the &#8220;Agreement&#8221;), is made by and between</font></div>
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman';">ASTRAZENECA AB, a company incorporated in Sweden under no. 556011-7482 with its registered office at SE-151 85 S&#246;dert&#228;lje, Sweden (&#8220;AstraZeneca&#8221;) and</font></div>
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman';">IONIS PHARMACEUTICALS, INC., a Delaware corporation, (formally known as Isis Pharmaceuticals, Inc.) having its principal place of business at 2855 Gazelle Court, Carlsbad,
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    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">and is made effective as of October 18<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup>, 2018 (the &#8220;Amendment Effective
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    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Recitals</font></div>
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    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">WHEREAS, the Parties desire to further amend and restate certain terms and conditions of the Agreement.</font></div>
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    <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">Agreement</font></div>
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    <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Any capitalized term not separately defined in this Amendment shall have the meaning ascribed to it in the Agreement.</font></div>
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              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">2.</font></td>
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    <div>&#160;</div>
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      <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Section 5.1.2. of the Agreement is hereby deleted in its entirety and replaced by the following:</font></div>
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    <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">&#8220;5.1.2. <font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Integrated Product Plans</u></font>.&#160; For
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Amendment Effective Date</u></font></font></div>
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    <div>&#160;</div>
    <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">This Amendment shall become effective on the Amendment Effective Date.</font></div>
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              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">4.</font></td>
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Entire Agreement</u></font></font></div>
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    <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">This Amendment, together with the Agreement, constitutes the entire agreement between the Parties with respect to the subject matter of the
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              <td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman';">5.</font></td>
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                <div><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;"><u>Execution</u></font></font></div>
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    <div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman';">THIS AMENDMENT IS EXECUTED by the authorized representatives of the parties as of the date first written above.</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">ASTRAZENECA AB</font> (publ.)</font></div>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman'; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</font></div>
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          <td style="width: 8%; vertical-align: top;">&#160;</td>
          <td style="width: 25%; vertical-align: top;">&#160;</td>
          <td style="width: 8%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">&#160;</td>
          <td style="width: 26%; vertical-align: top;">&#160;</td>
          <td style="width: 26%; vertical-align: top;">&#160;</td>
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            <div style="text-align: left; font-style: normal;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">/s/ <font style="font-style: italic;">Regina
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          <td style="width: 8%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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          <td style="width: 26%; vertical-align: top; border-bottom: 2px solid black;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">/s/ <font style="font-style: italic;">Brett Monia</font><br>
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          <td style="width: 26%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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          <td style="width: 8%; vertical-align: top;">&#160;</td>
          <td style="width: 25%; vertical-align: top;">&#160;</td>
          <td style="width: 8%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">&#160;</td>
          <td style="width: 26%; vertical-align: top;">&#160;</td>
          <td style="width: 26%; vertical-align: top;">&#160;</td>
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          <td style="width: 4%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
          <td style="width: 8%; vertical-align: top; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';">Name:</font></div>
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          <td style="width: 25%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Regina Fritsche Danielson</font></font></div>
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          <td style="width: 8%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">Brett Monia</font></font></div>
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          <td style="width: 4%; vertical-align: top;" colspan="1">&#160;</td>
          <td style="width: 8%; vertical-align: top;">&#160;</td>
          <td style="width: 25%; vertical-align: top;">&#160;</td>
          <td style="width: 8%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">&#160;</td>
          <td style="width: 26%; vertical-align: top;">&#160;</td>
          <td style="width: 26%; vertical-align: top;">&#160;</td>
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          <td style="width: 4%; vertical-align: top; padding-bottom: 2px;" colspan="1">&#160;</td>
          <td style="width: 8%; vertical-align: top; padding-bottom: 2px;">
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman';"><font style="font-size: 10pt; font-family: 'Times New Roman';">VP and Head of IMED CVRM</font></font></div>
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<DOCUMENT>
<TYPE>EX-10.70
<SEQUENCE>5
<FILENAME>exhibit10_70.htm
<DESCRIPTION>EXHIBIT 10.70
<TEXT>
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    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Final Execution Version</div>
    <div style="text-align: left; font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;"> <br>
    </div>
  </div>
  <div>
    <div style="text-align: right;"><font style="font-weight: bold; font-family: &quot;Times New Roman&quot;; font-size: 10pt;"><u>Exhibit 10.70</u></font></div>
    <div><br>
    </div>
    <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">CONFIDENTIAL TREATMENT REQUESTED</font></div>
    <div style="text-align: right;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">UNDER 17 C.F.R. &#167;&#167; 200.80(b)(4), 240.24B-2</font></div>
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    <div style="text-align: center;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">AMENDMENT NO. 4</font></div>
    <div>&#160;</div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">This Amendment No. 4 (the &#8220;Amendment&#8221;) to the Collaboration, License and Development Agreement dated December 7<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup>, 2012 (the &#8220;Agreement&#8221;), is made by and between</font></div>
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              <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">(1)</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">ASTRAZENECA AB, a company incorporated in Sweden under no. 556011-7482 with its registered office at SE-151 85 S&#246;dert&#228;lje, Sweden (&#8220;AstraZeneca&#8221;) and</font></div>
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      </div>
    </div>
    <div>&#160;</div>
    <div style="text-align: left;">
      <div>
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              <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">(2)</font></td>
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                <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">IONIS PHARMACEUTICALS, INC., a Delaware corporation, (formally known as Isis Pharmaceuticals, Inc.) having its principal place of business at 2855 Gazelle Court,
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    <div>&#160;</div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">and is made effective as of October 18<sup style="vertical-align: text-top; line-height: 1; font-size: smaller;">th</sup>, 2018 (the &#8220;Amendment
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    <div>&#160;</div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Recitals</font></div>
    <div>&#160;</div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">WHEREAS, the Parties desire to further amend and restate certain terms and conditions of the Agreement.</font></div>
    <div>&#160;</div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;">Agreement</font></div>
    <div>&#160;</div>
    <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">NOW, THEREFORE, in consideration of the mutual covenants contained in this Amendment, and other good and valuable consideration, the receipt and
        sufficiency of which are hereby acknowledged, the Parties, intending to be legally bound, agree as follows:</font></div>
    <div>&#160;</div>
    <div style="text-align: left;">
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              <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">1.</font></td>
              <td style="width: auto; vertical-align: top; text-align: left;">
                <div><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;; font-weight: bold;"><u>Definitions</u></font></font></div>
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    <div>&#160;</div>
    <div style="text-align: left; text-indent: 18pt;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Any capitalized term not separately defined in this Amendment shall have the meaning ascribed to it in the Agreement.</font></div>
    <div>&#160;</div>
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              <td style="width: 18pt; vertical-align: top;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">2.</font></td>
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        matter of the Agreement.&#160; The Agreement together with this Amendment and any prior Amendments thereto supersedes all prior agreements, whether written or oral, with respect to the subject matter of the Agreement, as amended.&#160; Each Party confirms
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    <div>&#160;</div>
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          <td style="width: 8%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top; width: 25%;">&#160;</td>
          <td style="width: 8%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">&#160;</td>
          <td style="width: 26%; vertical-align: top;">&#160;</td>
          <td style="width: 26%; vertical-align: top;">&#160;</td>
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        <tr>
          <td colspan="1" style="width: 4%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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          <td style="width: 8%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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          <td style="width: 26%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 8%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="vertical-align: top; width: 25%;">&#160;</td>
          <td rowspan="1" style="width: 8%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="vertical-align: top;" colspan="2">&#160;</td>
          <td rowspan="1" style="width: 26%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 26%; vertical-align: top;">&#160;</td>
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        <tr>
          <td colspan="1" style="width: 4%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          <td style="width: 8%; vertical-align: top; padding-bottom: 2px;">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Name:</font></div>
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          <td style="vertical-align: top; width: 25%; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Regina Fritsche Danielson</font></font></div>
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          <td style="vertical-align: top; padding-bottom: 2px;" colspan="2">
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          <td style="width: 26%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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          <td rowspan="1" colspan="1" style="width: 4%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 8%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="vertical-align: top; width: 25%;">&#160;</td>
          <td rowspan="1" style="width: 8%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="vertical-align: top;" colspan="2">&#160;</td>
          <td rowspan="1" style="width: 26%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 26%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td colspan="1" style="width: 4%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
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            <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">VP and Head of IMED CVRM</font></font></div>
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          <td style="width: 8%; vertical-align: top; padding-bottom: 2px;">&#160;</td>
          <td style="vertical-align: top; padding-bottom: 2px;" colspan="2">
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          <td style="width: 26%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: left;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;"><font style="font-size: 10pt; font-family: &quot;Times New Roman&quot;;">Chief Operating Officer</font></font></div>
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        </tr>

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<DOCUMENT>
<TYPE>EX-21.1
<SEQUENCE>6
<FILENAME>exhibit21_1.htm
<DESCRIPTION>EXHIBIT 21.1
<TEXT>
<html>
  <head>
    <title>&#160;</title>
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      <hr noshade="noshade" align="center" style="height: 4px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;">Exhibit&#160;21.1</div>
    <div style="text-align: right;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
    <div style="text-align: center;"><font style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">LIST OF SUBSIDIARIES FOR THE REGISTRANT</font></div>
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    <div style="text-align: center;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
    <div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Subsidiaries of Ionis Pharmaceuticals, Inc:</div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis USA Limited, a United Kingdom Limited Private Company</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Osprey Therapeutics, Inc., a Delaware Corporation</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Symphony GenIsis,&#160;Inc., a Delaware Corporation</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ionis Development (Ireland) Limited, an Ireland Limited Private Company</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea Therapeutics, Inc., a Delaware Corporation</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-family: 'Times New Roman', serif; font-size: 1pt;">&#160;</font>Akcea Therapeutics France SAS, a French Company</font></div>
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    <div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-family: 'Times New Roman', serif; font-size: 1pt;">&#160;</font>Akcea Therapeutics UK Limited, a United Kingdom
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<DOCUMENT>
<TYPE>EX-23.1
<SEQUENCE>7
<FILENAME>exhibit23_1.htm
<DESCRIPTION>EXHIBIT 23.1
<TEXT>
<html>
  <head>
    <title>&#160;</title>
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         Copyright 1995 - 2019 Broadridge -->
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  <div id="TRGRSegment:b8cd2a2a-2f7b-470b-8887-e5b31a337448">
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      <hr noshade="noshade" align="center" style="height: 4px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;">Exhibit&#160;23.1</div>
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    <div style="text-align: center;"><font style="font-family: 'Times New Roman'; font-size: 10pt; font-weight: bold;">CONSENT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM</font></div>
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      <div style="text-align: justify; font-family: &quot;Times New Roman&quot;,Times,serif; font-size: 10pt;">We consent to the incorporation by reference in the Registration Statement on Form&#160;S-3 (No.&#160; 333-217422) and in the related Prospectuses, as
        applicable, and in the Registration Statements on Form&#160;S-8 (Nos.&#160;333-05825, 333-55683, 333-40336, 333-59296, 333-91572, 333-106859, 333-116962, 333-125911, 333-133853, 333-142777, 333-151996, 333-160269, 333-168674, 333-176136, 333-184788,
        333-190408, 333-207900, and 333-219801) of Ionis Pharmaceuticals,&#160;Inc. of our reports dated March 1, 2019, with respect to the consolidated financial statements of Ionis Pharmaceuticals,&#160;Inc. and the effectiveness of internal control over financial
        reporting of Ionis Pharmaceuticals,&#160;Inc. included in this Annual Report (Form&#160;10-K) of Ionis Pharmaceuticals, Inc. for the year ended December&#160;31, 2018.</div>
    </div>
    <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
    <table cellspacing="0" cellpadding="0" id="z98fcb9444b034b6681b173ddeba446cf" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%; border-collapse: collapse;">

        <tr>
          <td style="width: 50.6%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 1pt;">&#160;</font><font style="font-family: 'Times New Roman'; font-size: 10pt;">/s/ ERNST&#160;&amp; YOUNG LLP</font></div>
          </td>
          <td style="width: 49.4%; vertical-align: top;"> <br>
          </td>
        </tr>
        <tr>
          <td style="width: 50.6%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
          </td>
          <td style="width: 49.4%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 50.6%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">San Diego, California</font></div>
          </td>
          <td style="width: 49.4%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 1pt;">&#160;</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 50.6%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">March 1, 2019</font></div>
          </td>
          <td style="width: 49.4%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 1pt;">&#160;</font></div>
          </td>
        </tr>

    </table>
    <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
    <div style="text-align: left;">
      <hr noshade="noshade" align="center" style="height: 2px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;"><font style="font-family: 'Times New Roman'; font-size: 10pt;"> </font></div>
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<DOCUMENT>
<TYPE>EX-31.1
<SEQUENCE>8
<FILENAME>exhibit31_1.htm
<DESCRIPTION>EXHIBIT 31.1
<TEXT>
<html>
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  <div id="TRGRSegment:27688458-8a95-448c-9822-a3a5e0da6065">
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      <hr noshade="noshade" align="center" style="height: 4px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;">Exhibit 31.1</div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">CERTIFICATION</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">I, Stanley T. Crooke, certify that:</font></div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="z5bd58330afcc44e489e3a7c6a2fe340f" class="DSPFListTable">

          <tr>
            <td style="width: 27pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 9pt;"><font style="font-family: Calibri; font-size: 10pt;">1.</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">I have reviewed this Annual Report on Form 10-K of Ionis Pharmaceuticals, Inc.;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="z40db2d8b367b457481bbffce71fb5c4c" class="DSPFListTable">

          <tr>
            <td style="width: 27pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 9pt;"><font style="font-family: Calibri; font-size: 10pt;">2.</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">Based on my knowledge, this annual report does not contain any untrue statement of a material fact or omit to state a material fact necessary to
                  make the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this annual report;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="z92841526707e4761bb1169fe6244b4ed" class="DSPFListTable">

          <tr>
            <td style="width: 27pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 9pt;"><font style="font-family: Calibri; font-size: 10pt;">3.</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">Based on my knowledge, the consolidated financial statements, and other financial information included in this annual report, fairly present in
                  all material respects the financial condition, consolidated results of operations and consolidated cash flows of the registrant as of, and for, the periods presented in this annual report;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="zafc77cad58d84462a549b8edd78691f1" class="DSPFListTable">

          <tr>
            <td style="width: 27pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 9pt;"><font style="font-family: Calibri; font-size: 10pt;">4.</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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:</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="z088974c956ba496882e3a072d0de8e3b" class="DSPFListTable">

          <tr>
            <td style="width: 45pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 27pt;"><font style="font-family: Calibri; font-size: 10pt;">a)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="zb9dc89c88d4b4ca1803115e32f3174c8" class="DSPFListTable">

          <tr>
            <td style="width: 45pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 27pt;"><font style="font-family: Calibri; font-size: 10pt;">b)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="z25a3ac111d5e48f8afc43074ef30f3b6" class="DSPFListTable">

          <tr>
            <td style="width: 45pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 27pt;"><font style="font-family: Calibri; font-size: 10pt;">c)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
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    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="zae55e117027e4df4857757dd92c4ecd6" class="DSPFListTable">

          <tr>
            <td style="width: 45pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 27pt;"><font style="font-family: Calibri; font-size: 10pt;">d)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="z55464a5de94d4663be410b4575664561" class="DSPFListTable">

          <tr>
            <td style="width: 27pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 9pt;"><font style="font-family: Calibri; font-size: 10pt;">5.</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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):</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="z6c3d2a0035f042dc98e44b7aeebf43bb" class="DSPFListTable">

          <tr>
            <td style="width: 45pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 27pt;"><font style="font-family: Calibri; font-size: 10pt;">a)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;" id="z05415ab6fefb48988a0b7c2bece5fbaa" class="DSPFListTable">

          <tr>
            <td style="width: 45pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 27pt;"><font style="font-family: Calibri; font-size: 10pt;">b)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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.</font></div>
            </td>
          </tr>

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    </div>
    <div style="text-align: justify;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;&#160;</font></div>
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        <tr>
          <td style="width: 41.39%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">Dated: March 1, 2019</font></div>
          </td>
          <td style="width: 58.61%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 41.39%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
          </td>
          <td style="width: 58.61%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 41.39%; vertical-align: top; border-bottom: #000000 2px solid;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">/s/ STANLEY T. CROOKE</font></div>
          </td>
          <td style="width: 58.61%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 41.39%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">Stanley T. Crooke, M.D., Ph.D.</font></div>
          </td>
          <td style="width: 58.61%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
          </td>
        </tr>
        <tr>
          <td style="width: 41.39%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt; font-style: italic;">Chief Executive Officer</font></div>
          </td>
          <td style="width: 58.61%; vertical-align: top;">
            <div style="text-align: left;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">&#160;</font></div>
          </td>
        </tr>

    </table>
    <div><br>
    </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-31.2
<SEQUENCE>9
<FILENAME>exhibit31_2.htm
<DESCRIPTION>EXHIBIT 31.2
<TEXT>
<html>
  <head>
    <title>&#160;</title>
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         Copyright 1995 - 2019 Broadridge -->
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  <div id="TRGRSegment:f325a129-9b94-442a-a705-509884803066">
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      <hr noshade="noshade" align="center" style="height: 4px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;">Exhibit 31.2</div>
    <div><br>
    </div>
    <div style="text-align: center;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">CERTIFICATION</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">I, Elizabeth L. Hougen, certify that:</font></div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zd619431a3b99471fba6525943c003200" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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            <td style="width: 27pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 9pt;"><font style="font-family: Calibri; font-size: 10pt;">1.</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">I have reviewed this Annual Report on Form 10-K of Ionis Pharmaceuticals, Inc.;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
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            <td style="width: 27pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 9pt;"><font style="font-family: Calibri; font-size: 10pt;">2.</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">Based on my knowledge, this annual report does not contain any untrue statement of a material fact or omit to state a material fact necessary to
                  make the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this annual report;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z512495ad196a4ee892b77f1b8a962a95" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

          <tr>
            <td style="width: 27pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 9pt;"><font style="font-family: Calibri; font-size: 10pt;">3.</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">Based on my knowledge, the consolidated financial statements, and other financial information included in this annual report, fairly present in
                  all material respects the financial condition, consolidated results of operations and consolidated cash flows of the registrant as of, and for, the periods presented in this annual report;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z77cfa0a3782c4861be7edcd208994ffd" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

          <tr>
            <td style="width: 27pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 9pt;"><font style="font-family: Calibri; font-size: 10pt;">4.</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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:</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zbe4a415ec4c3400f979554e6108646f3" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

          <tr>
            <td style="width: 45pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 27pt;"><font style="font-family: Calibri; font-size: 10pt;">a)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="zd64e9902f73744298a16a657c965f1f8" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

          <tr>
            <td style="width: 45pt; vertical-align: top; align: right;">
              <div style="text-align: left; margin-left: 27pt;"><font style="font-family: Calibri; font-size: 10pt;">b)</font></div>
            </td>
            <td style="width: auto; vertical-align: top;">
              <div style="text-align: justify;"><font style="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;</font></div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" class="DSPFListTable" id="z3237fc8b248a4c38bdde76c4f47ce019" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;">

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    <div style="text-align: center;"><font style="font-family: 'Times New Roman'; font-size: 10pt;">CERTIFICATION</font></div>
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                <div><font style="font-family: 'Times New Roman'; font-size: 10pt;">The Company&#8217;s Annual Report on Form 10-K for the year ended December 31, 2018, to which this Certification is attached as Exhibit 32.1 (the &#8220;Annual Report&#8221;), fully complies
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We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2018:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;One year or less&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;As illustrated above, at December 31, 2018, 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="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize all of these securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the balance sheet date.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At December 31, 2018, we had an ownership interest of less than 20 percent &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;in four private companies and two public companies with which we conduct business. 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text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;107,874&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by the U.S. Treasury&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;15,600&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(24&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;15,576&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;16,980&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(287&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;16,693&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total securities with a maturity of more than one year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;439,387&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;388&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,706&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;438,069&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total available-for-sale securities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,873,317&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;419&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4,068&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,869,668&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Equity securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total equity securities included in other current assets (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,212&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;137&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,349&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total available-for-sale and equity securities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,874,529&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;556&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4,068&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,871,017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Gross Unrealized&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Estimated&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Cost &lt;/font&gt;(1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Gains&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Losses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Fair Value&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Available-for-sale securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Corporate debt securities (2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;500,599&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(752&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;499,849&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by U.S. government agencies&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;83,926&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(212&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(740&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;64,810&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total securities with a maturity of more than one year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;268,401&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,969&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;266,440&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total available-for-sale securities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;911,594&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;14&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3,072&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;908,536&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We hold our available-for-sale securities at amortized cost.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Includes investments classified as cash equivalents on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize our equity securities at&lt;/font&gt; cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; on our consolidated balance sheet.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investments we consider to be temporarily impaired at December 31, 2018 are as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Less than 12 Months of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Temporary Impairment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;More than 12 Months of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Temporary Impairment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Total Temporary&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Impairment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Number of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Investments&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Estimated&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Fair Value&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Unrealized&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Losses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; 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font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,208&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,126,818&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3,144&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 16%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by U.S. government agencies&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;34,403&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(104&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;195,715&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(213&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 16%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by the U.S. Treasury&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;36&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; 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font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,413&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4,068&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We believe that the decline in value of our debt securities is temporary and primarily related to the change in market interest rates since purchase. We believe it is more likely than not that we will be able to hold these securities to maturity. Therefore, we anticipate full recovery of our debt securities&amp;#8217; amortized cost basis at maturity.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</invest:InvestmentTextBlock>
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Collaborative Arrangements and Licensing Agreements&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Strategic Partnership&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Biogen&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen&amp;#8217;s expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with spinal muscular atrophy, or SMA. In&lt;/font&gt; December 2017, we entered into a collaboration with Biogen to identify &lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;new antisense medicines for the treatment of SMA&lt;/font&gt;. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Additionally, we and Biogen are currently developing six other medicines to treat neurodegenerative diseases under these collaborations, including IONIS-SOD1&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; for ALS, IONIS-MAPT&lt;/font&gt;&lt;sub&gt;Rx &lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;for Alzheimer&amp;#8217;s disease&lt;/font&gt;&lt;sub&gt;,&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; IONIS-C9&lt;/font&gt;&lt;sub&gt;Rx &lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;for ALS, and IONIS-BIIB6&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, IONIS-BIIB7&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; and IONIS-BIIB8&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; to treat undisclosed neurodegenerative diseases. In addition to these medicines, we and Biogen are evaluating numerous additional targets to develop medicines to treat neurological diseases. In April 2018, we entered into a new strategic collaboration for the treatment of neurological diseases with Biogen. From inception through December 2018, we have received over $2.0 billion from our Biogen collaborations, including $1 billion we received from Biogen in the second quarter of 2018 for our 2018 strategic neurology collaboration.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Spinal Muscular Atrophy Collaborations&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;SPINRAZA&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In January 2012, we entered into a collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA. Biogen reported in &lt;/font&gt;January 2019 that SPINRAZA was approved in over 40 countries around the world. In February 2019, SPINRAZA was approved in China. Biogen is responsible for global SPINRAZA commercial activities.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;From inception through December 2018, we earned more than $785 million in total revenue under our SPINRAZA collaboration, including more than $350 million in revenue from SPINRAZA royalties and more than $435 million in R&amp;amp;D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on any net sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible for all further global development, regulatory and commercialization activities and costs for SPINRAZA.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Over the course of our SPINRAZA collaboration, we identified two performance obligations, which were to perform R&amp;amp;D services and to deliver the SPINRAZA license to Biogen. As we achieved milestone payments for our R&amp;amp;D services, we included these amounts in our transaction price for our R&amp;amp;D services performance obligation. We recognized revenue for our R&amp;amp;D services performance obligation over our period of performance through December 2016. We recognized the $75 million license fee for SPINRAZA as revenue when we delivered the license to Biogen in July 2016 because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We also earned additional milestone payments subsequent to delivering the license to Biogen that we recognized in full in the period each milestone payment became probable because we did not have a performance obligation related to each milestone payment. For example, we received $90 million of milestone payments for the approval of SPINRAZA in the EU and Japan in 2017 and recognized the full amounts into revenue in the period Biogen achieved the milestone events.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;New antisense medicines for the treatment of SMA&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In December 2017, we entered into a collaboration agreement with Biogen to &lt;/font&gt;identify &lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;new antisense medicines for the treatment of SMA&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. &lt;/font&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Biogen will have the option to license therapies arising out of this collaboration following the completion of preclinical studies. Upon licensing, Biogen &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;will be responsible for all further global development, regulatory and commercialization activities and costs for such therapies&lt;/font&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. Under the collaboration agreement, we received a&amp;#160;&lt;/font&gt;$25 million&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;upfront payment in December 2017. We will receive development and regulatory milestone payments from Biogen if new medicines advance towards marketing approval. &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In total over the term of our collaboration, we are eligible to receive up to $1.2 billion in license fees, milestone payments and other payments, including up to $80 million for the achievement of development milestones, up to $180 million for the achievement of commercialization milestones and up to $800 million for the achievement of sales milestones. In addition, we are eligible to receive tiered royalties &lt;/font&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;from the mid-teens to &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;mid-20 percent range &lt;/font&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;on net sales.&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; We will achieve the next payment of up to $60 million&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;for the license of a medicine under this collaboration. &lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for Biogen. We determined the transaction price to be the $25 million upfront payment we received when we entered into the collaboration. We allocated the transaction price to our single performance obligation. We are recognizing revenue for our R&amp;amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; currently estimate we will satisfy our performance obligation in&lt;/font&gt; December 2020.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Neurology Collaborations&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;2018 Strategic Neurology&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In April 2018, we and Biogen entered into a new strategic collaboration to develop novel antisense medicines for a broad range of neurological diseases and entered into a SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for these diseases for 10 years. We are responsible for the identification of antisense drug candidates based on selected targets&lt;/font&gt;.&amp;#160;Biogen is responsible for conducting IND-enabling toxicology studies for the selected target. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Biogen will have the option to license the selected target &lt;/font&gt;after it completes the IND-enabling toxicology study. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;If Biogen exercises its option for a medicine, it will assume &lt;/font&gt;all &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;further global development, regulatory and commercialization responsibilities and costs for that medicine.&amp;#160;&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In the second quarter of 2018, we received &lt;/font&gt;$1 billion from Biogen, comprised of $625 million to purchase our stock at an approximately 25 percent cash premium and $375 million in an upfront payment. &lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are eligible to receive up to $270 million in milestone payments for each medicine that achieves marketing approval. &lt;/font&gt;In addition, we are eligible to receive tiered royalties &lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;up to the 20 percent&lt;/font&gt; range &lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;on net sales.&lt;/font&gt; From inception through December 2018, we have received over $1 billion in payments under this collaboration, including $15 million we received in the fourth quarter of 2018 for advancing two targets under this collaboration. We will achieve the next payment of $7.5 million if Biogen designates a target&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; under this collaboration. &lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, &lt;/font&gt;we identified one performance obligation, which was to perform R&amp;amp;D services for Biogen.&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; We determined our transaction price to be $552 million, comprised of $375 million from the upfront payment and $177 million for the premium paid by Biogen for its purchase of our common stock.&lt;/font&gt; We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of marketability discount. We included a lack of marketability discount in our valuation of the premium because Biogen received restricted shares. We allocated the transaction price to our single performance obligation. In the fourth quarter of 2018, we received $15 million in milestone payments when we advanced &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;two &lt;/font&gt;targets under this collaboration. We added these payments to our transaction price for our R&amp;amp;D services performance obligation. We are recognizing revenue for our R&amp;amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; currently estimate we will satisfy our performance obligation in &lt;/font&gt;June 2028.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;2013 Strategic Neurology&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In September&amp;#160;2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen will have the option to license antisense medicines after Phase 2 proof of concept. In October 2016, we expanded our collaboration to include additional research activities we will perform. If Biogen exercises its option for a medicine, it will assume all further global development, regulatory and commercialization responsibilities and costs for that medicine. We are currently advancing five medicines, IONIS-SOD1&lt;sub&gt;Rx&lt;/sub&gt;, IONIS-C9&lt;sub&gt;Rx&lt;/sub&gt;, IONIS-BIIB6&lt;sub&gt;Rx&lt;/sub&gt;, IONIS-BIIB7&lt;sub&gt;Rx&lt;/sub&gt; and IONIS-BIIB8&lt;sub&gt;Rx&lt;/sub&gt; under this collaboration. In the fourth quarter of 2018, Biogen licensed IONIS-SOD1&lt;sub&gt;Rx&lt;/sub&gt;, and as a result Biogen now is responsible for all further global development, regulatory and commercialization activities and costs for IONIS-SOD1&lt;sub&gt;Rx&lt;/sub&gt;.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone payments, license fees and royalty payments for all medicines developed through this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug discovery and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee and milestone payments per program. The $260 million per program consists of approximately $60 million in development milestones, including amounts related to the cost of clinical trials, and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any antisense medicines developed under this collaboration. From inception through December 2018, we have received over $210 million in upfront fees, milestone payments and other payments under this collaboration, not including a $5 million milestone payment we earned in the fourth quarter of 2018 for Biogen&amp;#8217;s initiation of a Proof of Concept study for IONIS-SOD1&lt;sub&gt;Rx &lt;/sub&gt;which we received in the first quarter of 2019. We will achieve the next payment of up to $10 million if we advance a program under this collaboration.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of our strategic neurology collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for Biogen. At inception, we determined the transaction price to be the $100 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&amp;amp;D services, we include these amounts in our transaction price for our R&amp;amp;D services performance obligation. We are recognizing revenue for our R&amp;amp;D services performance obligation based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. &lt;/font&gt;We&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; currently estimate we will satisfy our performance obligation in&lt;/font&gt; September 2019. From inception through December &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2018&lt;/font&gt;, we have included $145 million in total payments in the transaction price for our R&amp;amp;D services performance obligation. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In the third quarter of 2018, we earned a $10 million milestone payment when Biogen initiated a Phase 1 study of IONIS-C9&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. We concluded that the milestone payment was not related to our R&amp;amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any performance obligations related to this milestone payment.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We identified a second performance obligation upon Biogen&amp;#8217;s license of IONIS-SOD1&lt;sub&gt;Rx&lt;/sub&gt; in the fourth quarter of 2018 because the license we granted to Biogen is distinct from our other performance obligation. We recognized the $35 million license fee for IONIS-SOD1&lt;sub&gt;Rx&lt;/sub&gt; as revenue at that time because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen. Additionally, in the fourth quarter of 2018 we &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;earned a $5 million milestone when Biogen initiated a Proof-of-Concept study for IONIS-SOD1&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. We concluded that the milestone payment was not related to our R&amp;amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the fourth quarter of 2018 because we do not have any performance obligations related to this milestone payment.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Neurology&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In December&amp;#160;2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense medicines to up to three targets to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the programs through the completion of the first Phase 2 study for each program. We are currently advancing IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt; for Alzheimer&amp;#8217;s disease under this collaboration. If Biogen exercises its option for a medicine, it will assume all further global development, regulatory and commercialization responsibilities and costs for that medicine.&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Under the terms of the agreement, we received an upfront payment of $30 million. Over the term of the collaboration, we are eligible to receive up to $210 million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. The $210 million per program consists of up to $10 million in development milestone payments, plus a mark-up on the cost estimate of the Phase 1 and 2 studies and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each of the three programs. From inception through December 2018, we have received $58 million in milestone payments and upfront fees under this collaboration. We will achieve the next payment of $7.5 &lt;/font&gt;million if we continue to advance IONIS-MAPT&lt;sub&gt;Rx&lt;/sub&gt;.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for Biogen. At inception, we determined the transaction price to be the $30 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&amp;amp;D services, we include these amounts in our transaction price for our R&amp;amp;D services performance obligation. We are recognizing revenue for our R&amp;amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; currently estimate we will satisfy our performance obligation in &lt;/font&gt;December 2020. From inception through December&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; 2018&lt;/font&gt;, we have included $40 million in total payments in the transaction price for our R&amp;amp;D services performance obligation.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;SPINRAZA royalties (commercial revenue)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;237.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;112.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;137.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;150.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;248.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total revenue from our relationship with Biogen&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;375.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;263.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;249.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;63&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;51&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;67&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our &lt;/font&gt;consolidated balance sheet at &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 31, 2018 and 2017 included deferred revenue of $580.9 million and $93.6 million, respectively, related to our relationship with Biogen.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Research, Development and Commercialization Partners&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;AstraZeneca&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Cardiac, Renal and Metabolic Diseases Collaboration&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In July 2015, we and AstraZeneca formed a collaboration to discover and develop antisense therapies for treating cardiac, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed three medicines from us: IONIS-AZ4-2.5-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, a medicine we designed to treat cardiovascular disease and our first &lt;/font&gt;medicine that combines our Generation 2.5 and&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; LICA technology, IONIS-AZ5-2.5&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, a medicine we designed to &lt;/font&gt;treat a genetically associated form of kidney disease and &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;IONIS-AZ6-2.5-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, a medicine we designed to &lt;/font&gt;inhibit an undisclosed target to treat patients with nonalcoholic steatohepatitis, or NASH&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. AstraZeneca is responsible for all further global development, regulatory and commercialization activities and costs for each of the medicines it has licensed and any other future medicines AstraZeneca licenses.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Under the terms of the agreement, we received a $65 million upfront payment. We are eligible to receive license fees and milestone payments of up to more than $4 billion as medicines under this collaboration advance, including up to $1.1 billion for the achievement of development milestones and up to $2.9 billion for regulatory milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. From inception through December 2018, we have received over $165 million in upfront fees, license fees, milestone payments, and other payments under this collaboration, including a $10 million milestone payment we earned in the third quarter of 2018 when AstraZeneca initiated a Phase 1 trial for IONIS-AZ4-2.5-L&lt;sub&gt;Rx&lt;/sub&gt;. We will achieve the next payment of $10 million under this collaboration if we advance a medicine under this collaboration&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for AstraZeneca. We determined the transaction price to be the $65 million upfront payment we received and we allocated it to our single performance obligation. We are recognizing revenue for our R&amp;amp;D services performance obligation as we perform services based on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; currently estimate we will satisfy this performance obligation in&lt;/font&gt; August 2021. As we achieve milestone payments for our R&amp;amp;D services, we include these amounts in our transaction price for our R&amp;amp;D services performance obligation. From inception through December&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; 2018&lt;/font&gt;, we have included $90 million in payments in the transaction price for our R&amp;amp;D services performance obligation.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We identified separate performance obligations upon AstraZeneca&amp;#8217;s license of IONIS-AZ5-2.5&lt;sub&gt;Rx&lt;/sub&gt; and IONIS-AZ6-2.5-L&lt;sub&gt;Rx&lt;/sub&gt; in the first quarter of 2018 because the licenses are distinct from our other performance obligation and each other. We recognized each $30 million license fee in the first quarter of 2018 because AstraZeneca had full use of the licenses without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the licenses after we delivered them to AstraZeneca.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In the third quarter of 2018, we earned a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of IONIS-AZ4-2.5-L&lt;sub&gt;Rx&lt;/sub&gt;. We concluded that the milestone payment was not related to our R&amp;amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any performance obligations related to this milestone payment.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Oncology Collaboration&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In December&amp;#160;2012, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense medicines to treat cancer.&amp;#160;As part of the agreement, we granted AstraZeneca an exclusive license to develop and commercialize &lt;/font&gt;danvatirsen (formerly &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;IONIS-STAT3-2.5&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;) for the treatment of cancer. AstraZeneca is now responsible for all global development, regulatory and commercialization activities for &lt;/font&gt;danvatirsen&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. We and AstraZeneca have evaluated &lt;/font&gt;danvatirsen&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; in people with head and neck cancer, advanced lymphoma and advanced metastatic hepatocellular carcinoma. AstraZeneca is evaluating &lt;/font&gt;danvatirsen&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; in combination with durvalumab, AstraZeneca&amp;#8217;s PD-L1 blocking drug, in people with head and neck cancer, metastatic bladder cancer and metastatic non-small cell lung cancer. We and AstraZeneca also established an oncology research program. AstraZeneca has the option to license medicines resulting from the program, and if AstraZeneca exercises its option for a medicine, it will be responsible for all further global development, regulatory and commercialization activities and costs for such medicine. In the fourth quarter of 2018, we added &lt;/font&gt;IONIS-AZ7-2.5&lt;sub&gt;Rx&lt;/sub&gt; to our preclinical pipeline, a second drug under our oncology collaboration.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Under the terms of this agreement, we received $31 million in upfront payments. We are eligible to receive milestone payments and license fees from AstraZeneca as programs advance in development. If AstraZeneca successfully develops &lt;/font&gt;danvatirsen&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; and another medicine under the research program, we could receive license fees and milestone payments of up to more than $450 million, including up to $152 million for the achievement of development milestones and up to $275 million for the achievement of regulatory milestones.&amp;#160;In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any medicines resulting from these programs. From inception through December 2018, we have received over $125 million in upfront fees, milestone payments, and other payments under this oncology collaboration, including nearly $30 million in milestone payments we achieved when AstraZeneca advanced &lt;/font&gt;danvatirsen and IONIS-AZ7-2.5&lt;sub&gt;Rx&lt;/sub&gt;, in the fourth quarter of 2018. We &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;will achieve the next payment of up to $25 million &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;if we advance a medicine under our cancer research program with AstraZeneca.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, we identified four performance obligations. We determined the transaction price to be the $31 million upfront payments we received. We allocated the transaction price based on the estimated stand-alone selling price of each of our performance obligations and recognized the associated revenue over the period of our performance. We recognized revenue for three of our obligations over our period of performance, which concluded in March 2014. Our remaining performance obligation was to perform R&amp;amp;D services. We allocated $7.6 million to this performance obligation and recognized the associated revenue over the period of our performance, which ended in February 2018. As we achieved milestone payments for our R&amp;amp;D services, we included these amounts in our transaction price for our R&amp;amp;D services performance obligation.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In the fourth quarter of 2018, we earned a $17.5 million milestone payment and a $10 million milestone payment when AstraZeneca advanced two programs under our collaboration. We recognized these milestone payments in full in the fourth quarter because we do not have any performance obligations related to these milestone payments.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;41.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;20&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our &lt;/font&gt;consolidated balance sheet at &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 31, 2018 and 2017 included deferred revenue of $40.1 million and $57.7 million, respectively, related to our relationship with AstraZeneca.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Bayer&lt;/div&gt;&lt;div style="background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; for the prevention of thrombosis. We were responsible for completing a Phase 2 study of IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; in people with end-stage renal disease on hemodialysis. Under the terms of the agreement, we received a $100 million upfront payment in the second quarter of 2015. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; and to initiate development of IONIS-FXI-L&lt;sub&gt;Rx&lt;/sub&gt;, which Bayer licensed. In conjunction with the decision to advance these programs, we received a $75 million payment from Bayer. We are conducting a Phase 2b study evaluating IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; in people with end-stage renal disease on hemodialysis to finalize dose selection. Additionally, we are developing IONIS-FXI-L&lt;sub&gt;Rx&lt;/sub&gt; through Phase 1. Following these studies and Bayer&amp;#8217;s decision to further advance these programs, Bayer will be responsible for all global development, regulatory and commercialization activities and costs for both medicines.&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are eligible to receive additional milestone payments as each medicine advances toward the market. In total over the term of this collaboration, we are eligible to receive up to $385 million in license fees, milestone payments and other payments, including up to $125 million for the achievement of development milestones and up to $110 million for the achievement of commercialization milestones. In addition, we are eligible to receive tiered royalties in the low to high 20 percent range on gross margins of both medicines combined. From inception through December 2018, we have received over $175 million from our Bayer collaboration. We will achieve the next payment of $10 million if a program advances under this collaboration.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, we identified three performance obligations. We determined the transaction price to be the $100 million upfront payment we received. We allocated the transaction price based on the relative stand-alone selling prices of each of our performance obligations and recognized the associated revenue as follows:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognized $91.2 million for the exclusive license of IONIS-FXI&lt;sub&gt;Rx &lt;/sub&gt;in May 2015 because Bayer &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;had full use of the license without any continuing involvement from us&lt;/font&gt;.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognized $4.3 million for the R&amp;amp;D services for IONIS-FXI&lt;sub&gt;Rx&lt;/sub&gt; over the period of our performance, which ended in November 2016.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We allocated $4.5 million for API, which we are recognizing into revenue as we deliver the API.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In February 2017, when we amended our collaboration with Bayer, we identified two new performance obligations&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, one for the license of IONIS-FXI-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; and one for R&amp;amp;D services&lt;/font&gt;. We determined the transaction price to be the $75 million payment. We allocated $64.9 million to &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;the license of IONIS-FXI-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; based on its estimated stand-alone selling price and recognized the associated revenue upon our delivery of the license in the first quarter of 2017. We allocated $10.1 million to our R&amp;amp;D services performance obligation based on an estimated stand-alone selling price. &lt;/font&gt;We are recognizing revenue for our R&amp;amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; currently estimate we will satisfy our &lt;/font&gt;R&amp;amp;D services &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;performance obligation in&lt;/font&gt; May 2019.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;67.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;13&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our &lt;/font&gt;consolidated balance sheet at &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 31, 2018 and 2017 included deferred revenue of $4.3 million and $9.3 million, respectively, related to our relationship with Bayer.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;GSK&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In March&amp;#160;2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop new medicines against targets for rare and serious diseases, including infectious diseases and some conditions causing blindness. Under the terms of the agreement, we received upfront payments of $35 million.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;GSK is advancing two medicines targeting hepatitis B virus, or HBV, under our collaboration: IONIS-HBV&lt;sub&gt;Rx&lt;/sub&gt;&amp;#160;and IONIS-HBV-L&lt;sub&gt;Rx&lt;/sub&gt;. GSK is currently conducting Phase 2 studies for both of these medicines, which we designed to reduce the production of viral proteins associated with HBV infection. GSK has the exclusive option to license the medicines resulting from this alliance at Phase 2 proof-of-concept for a license fee.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Under our agreement, if GSK successfully develops these medicines and achieves pre-agreed sales targets, we could receive license fees and milestone payments of $262 million, including up to $47.5 million for the achievement of development milestones, up to $120 million for the achievement of regulatory milestones and up to $70 million for the achievement of commercialization milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that GSK successfully commercializes under this alliance. From inception through December 2018, we have received more than $162 million in payments under this alliance with GSK. We will achieve the next payment of up to $25 million if GSK licenses a medicine under this program.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for GSK. We determined the transaction price to be the $35 million upfront payments we received and allocated it to our single performance obligation. As we achieved milestone payments for our R&amp;amp;D services, we included these amounts in our transaction price for our R&amp;amp;D services performance obligation. We recognized revenue for our R&amp;amp;D services performance obligation over our period of performance, which ended in March 2015. We do not have any remaining performance obligations under our collaboration with GSK, however we can still earn additional payments and royalties as GSK advances these medicines.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;14.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;17.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&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="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We did not have any deferred revenue from our relationship with GSK at December 31, 2018 or December 31, 2017.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Janssen Biotech, Inc.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In December&amp;#160;2014, we entered into a collaboration agreement with Janssen Biotech, Inc. to discover and develop antisense medicines that can be locally administered, including oral delivery, to treat autoimmune disorders of the gastrointestinal tract. Janssen has the option to license medicines from us through the designation of a development candidate for up to three programs. Under our collaboration, Janssen licensed IONIS-JBI1-2.5&lt;sub&gt;Rx&lt;/sub&gt; in July 2016 and IONIS-JBI2-2.5&lt;sub&gt;Rx&lt;/sub&gt; in November 2017. Janssen is currently conducting a Phase 1 study of IONIS-JBI1-2.5&lt;sub&gt;Rx&lt;/sub&gt; and IONIS-JBI2-2.5&lt;sub&gt;Rx&lt;/sub&gt; is in preclinical development. Prior to option exercise we are responsible for the discovery activities to identify development candidates. If Janssen exercises an option for any of the programs, it will be responsible for the global development, regulatory and commercial activities under that program. Under the terms of the agreement, we received $35 million in upfront payments. We are eligible to receive up to more than $800 million in license fees and milestone payments for these programs, including up to $175 million for the achievement of development milestones, up to $440 million for the achievement of regulatory milestones and up to $180 million for the achievement of commercialization milestones. From inception through December 2018, we have received over $75 million, including $15 million in license fees when Janssen licensed IONIS-JBI1-2.5&lt;sub&gt;Rx&lt;/sub&gt; and IONIS-JBI2-2.5&lt;sub&gt;Rx&lt;/sub&gt; from us. We also received $5 million in January 2018 for the initiation of a Phase 1 study of IONIS-JBI1-2.5&lt;sub&gt;Rx &lt;/sub&gt;in late 2017. In addition, we are eligible to receive tiered royalties up to the near teens on net sales from any medicines resulting from this collaboration. We will achieve the next payment of $5 million if Janssen continues to advance a target under this collaboration.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for Janssen. We determined the transaction price to be the $35 million upfront payments we received. We allocated the &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$35 million&lt;/font&gt; to our single performance obligation. As we achieved milestone payments for our R&amp;amp;D services, we included these amounts in our transaction price for our R&amp;amp;D services performance obligation. We recognized revenue for our R&amp;amp;D services performance obligation over our period of performance, which ended in November 2017.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We identified separate performance obligations each time Janssen licensed one of our medicines under our collaboration because the licenses we granted to Janssen were distinct from our other performance obligations. We recognized the $10 million license fee for IONIS-JBI1-2.5&lt;sub&gt;Rx&lt;/sub&gt; in July 2016 and $5 million for the license of IONIS-JBI2-2.5&lt;sub&gt;Rx&lt;/sub&gt; in November 2017, because Janssen had full use of the licenses without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the licenses after we delivered them to Janssen.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Janssen (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;36.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;24.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We did not have any deferred revenue from our relationship with Janssen at December 31, 2018 and 2017.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Roche&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Huntington&amp;#8217;s Disease&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In April&amp;#160;2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to develop treatments for Huntington&amp;#8217;s disease, or HD, based on our antisense technology. Roche had the option to license the medicines from us through the completion of the first Phase 1 trial. Under the agreement, we are responsible for the discovery and development of an antisense medicine targeting huntingtin, or HTT, protein. We evaluated a medicine targeting HTT, IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt;, in a Phase 1/2 clinical study in people with early stage HD.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In December 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license IONIS-HTT&lt;sub&gt;Rx &lt;/sub&gt;and is now responsible for the global development, regulatory and commercialization activities for IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt;. Under the terms of the agreement, we received an upfront payment of $30 million in April&amp;#160;2013.&amp;#160;In December 2016, we updated development activities for IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt; and as a result we were eligible for an additional $3 million payment, which we achieved in 2017. We are eligible to receive up to $365 million in a license fee and milestone payments including up to $70 million for the achievement of development milestones, up to $170 million for the achievement of regulatory milestones and up to $80 million for the achievement of commercialization milestones. In addition, we are eligible to receive up to $136.5 million in milestone payments for each additional medicine successfully developed.&amp;#160;We are also eligible to receive tiered royalties up to the mid-teens on any net sales of any product resulting from this alliance. From inception through December 2018, we have received over $112 million in upfront fees, milestone payments and license fees for advancing IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt;, not including $35 million in milestone payments we earned in the first quarter of 2019 when Roche dosed the first patient in a Phase 3 study for IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt;. We will achieve the next payment of $15 million if Roche advances IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt;.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for Roche. We determined the transaction price to be the $30 million upfront payment we received and allocated it to our single performance obligation. As we achieved milestone payments for our R&amp;amp;D services, we included these amounts in our transaction price for our R&amp;amp;D services performance obligation. We recognized revenue for our R&amp;amp;D services performance obligation over our period of performance, which ended in September 2017.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We identified a second performance obligation upon Roche&amp;#8217;s license of IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt; in the fourth quarter of 2017 because the license we granted to Roche is distinct from our other performance obligation. We recognized the $45 million license fee for IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt; as revenue at that time because Roche had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Roche.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We do not have any remaining performance obligations related to IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt; under this collaboration with Roche, however we can still earn additional payments and royalties as Roche advances IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt;.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;IONIS-FB-L&lt;/font&gt;&lt;sub&gt;&lt;font style="background-color: #FBFBFB;"&gt;Rx&lt;/font&gt;&lt;/sub&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; for Complement-Mediated Diseases&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In October 2018, we entered into a collaboration agreement with Roche to&lt;/font&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; develop IONIS-FB-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;for the treatment of complement-mediated diseases. The first indication we plan to pursue is the treatment of patients with Geographic Atrophy, or GA, the advanced stage of dry age-related macular degeneration, or AMD. We are responsible for conducting a Phase 2 study in patients with dry AMD. In addition, we are exploring the medicine in a severe and rare renal indication.&amp;#160;&lt;/font&gt;Roche&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;has the option to license IONIS-FB-L&lt;/font&gt;&lt;sub&gt;&lt;font style="background-color: #FBFBFB;"&gt;Rx&lt;/font&gt;&lt;/sub&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;at the completion of these studies. Upon licensing,&amp;#160;&lt;/font&gt;Roche &lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;will be responsible for all further global development, regulatory and commercialization activities and costs.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Under the terms of this agreement, we received a&amp;#160;&lt;/font&gt;$75 million&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;upfront payment in October 2018. We are eligible to receive up to&amp;#160;&lt;/font&gt;$684 million&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;in development, regulatory and sales milestone payments and license fees. In addition, we are also eligible to receive tiered royalties from the high teens to twenty percent on net sales. We will achieve the next payment of $20 million when we advance &lt;/font&gt;the Phase 2 study in patients with dry AMD&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;amp;D services for Roche. We determined the transaction price to be the $75 million upfront payment we received and allocated it to our single performance obligation. We are recognizing revenue for our R&amp;amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; currently estimate we will satisfy our performance obligation in &lt;/font&gt;December 2022.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;55.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our &lt;/font&gt;consolidated balance sheet at &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 31, 2018 included deferred revenue of $72.6 million related to our relationship with Roche. We did not have any deferred revenue related to our relationship with Roche at December 31, 2017.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic; font-weight: bold;"&gt;Akcea Collaborations&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following collaboration agreements relate to Akcea, our majority-owned affiliate. Our consolidated results include all the revenue earned and cash received under these collaboration agreements. We reflect the noncontrolling interest attributable to other owners of Akcea&amp;#8217;s common stock in a separate line on the statement of operations and in a separate line within stockholders&amp;#8217; equity in our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Novartis&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In January 2017, we and Akcea initiated a collaboration with Novartis to develop and commercialize AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt; and AKCEA-APOCIII-L&lt;sub&gt;Rx&lt;/sub&gt;.&lt;sub&gt;&amp;#160;&lt;/sub&gt;Under the collaboration agreement, Novartis has an exclusive option to further develop and commercialize AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt; and AKCEA-APOCIII-L&lt;sub&gt;Rx&lt;/sub&gt;. Akcea is responsible for completing a Phase 2 program, conducting an end-of-Phase 2 meeting with the FDA and providing initial quantities of API for each medicine. If Novartis exercises an option for either of these medicines, Novartis will be responsible for all further global development, regulatory and co-commercialization activities and costs for such medicine.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea received a $75 million upfront payment in the first quarter of 2017, of which it retained $60 million and paid us $15 million as a sublicense fee. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In February 2019, Novartis licensed AKCEA-APO(a)-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt; and we earned a $150 million license fee. Akcea will pay us $75 million as a sublicense fee in 2.8 million shares of Akcea common stock. Novartis is responsible for conducting and funding all future development, regulatory and commercialization activities for AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt;, including a global pivotal cardiovascular outcomes study, for which planning and initiation activities are underway.&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;If Novartis exercises its option for AKCEA-APOCIII-L&lt;sub&gt;Rx&lt;/sub&gt;, Novartis will pay Akcea a license fee equal to $150 million. In addition, for AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt;, Akcea is eligible to receive up to $675 million in milestone payments, including $25 million for the achievement of a development milestone, up to $290 million for the achievement of regulatory milestones and up to $360 million for the achievement of commercialization milestones. In addition, for AKCEA-APOCIII-L&lt;sub&gt;Rx&lt;/sub&gt;, Akcea is eligible to receive up to $530 million in milestone payments, including $25 million for the achievement of a development milestone, up to $240 million for the achievement of regulatory milestones and up to $265 million for the achievement of commercialization milestones. Akcea is also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt; and AKCEA-APOCIII-L&lt;sub&gt;Rx&lt;/sub&gt;. Akcea will pay 50 percent of these license fees, milestone payments and royalties to us as a sublicense fee.&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;In connection with Novartis&amp;#8217; license of AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt;, Akcea and Novartis established a more definitive framework under which the companies would negotiate the co-commercialization of AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt; in selected markets. Included in this framework is an option by which Novartis could solely commercialize AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt; in exchange for Novartis paying Akcea increased commercial milestone payments based on sales of AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt;.&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; Akcea may co-commercialize IONIS-APOCIII-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; if licensed and commercialized by Novartis in selected markets through its specialized sales force under terms and conditions to be negotiated with Novartis in the future.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6 million shares of our common stock for $100 million in the first quarter of 2017. As part of the SPA, Novartis was required to purchase $50 million of Akcea&amp;#8217;s common stock at the IPO price or our common stock at a premium if an IPO did not occur by April 2018. Under the SPA, in July 2017, Novartis purchased $50 million of Akcea&amp;#8217;s common stock in a separate private placement concurrent with the completion of its IPO at a price per share equal to the IPO price.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At the commencement of this collaboration, we identified four separate performance obligations:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D services for AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt;;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D services for AKCEA-APOCIII-L&lt;sub&gt;Rx&lt;/sub&gt;;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;API for AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt;; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;API for AKCEA-APOCIII-L&lt;sub&gt;Rx&lt;/sub&gt;.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We determined that the R&amp;amp;D services for each medicine and the API for each medicine were distinct from our other performance obligations.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We determined our transaction price to be $108.4 million, comprised of the following:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$75 million from the upfront payment;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$28.4 million for the premium paid by Novartis for its purchase of our common stock at a premium in the first quarter of 2017; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$5.0 million for the potential premium Novartis would have paid if they purchased our common stock in the future.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$64.0 million for the R&amp;amp;D services for &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;AKCEA-APO(a)-L&lt;/font&gt;&lt;sub&gt;&lt;font style="font-family: 'Times New Roman';"&gt;Rx&lt;/font&gt;&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;;&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$40.1 million for the R&amp;amp;D services for &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;AKCEA-APOCIII-L&lt;/font&gt;&lt;sub&gt;&lt;font style="font-family: 'Times New Roman';"&gt;Rx&lt;/font&gt;&lt;/sub&gt;; &lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$1.5&lt;/font&gt; million for the delivery of AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt; API; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$2.8&lt;/font&gt; million for the delivery of AKCEA-APOCIII-L&lt;sub&gt;Rx&lt;/sub&gt; API.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are recognizing revenue related to the R&amp;amp;D services for the AKCEA-APO(a)-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; and AKCEA-APOCIII-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; performance obligations as we perform services &lt;/font&gt;based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. &lt;/font&gt;We&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; satisfied the significant portion of our performance obligation for AKCEA-APO(a)-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; in December 2018 and we currently estimate we will satisfy the remainder by mid-2019. &lt;/font&gt;We&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; currently estimate we will satisfy the significant portion of our performance obligation for AKCEA-APOCIII-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; by mid-2020 with the remainder by the end of 2019. We recognized the amount attributed to the API supply for AKCEA-APO(a)-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; when we delivered it to Novartis in 2017. We recognized the amount attributed to the API supply for AKCEA-APOCIII-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; when we delivered it to Novartis in May 2018.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea is responsible for the development activities under this collaboration. As such, Akcea is recognizing the associated revenue in its statement of operations, and we reflect all of Akcea&amp;#8217;s revenue in our consolidated results. Akcea pays us sublicense fees for payments that it receives under the collaboration and we recognize those fees as revenue in our Ionis Core operating segment results and Akcea recognizes the fees as R&amp;amp;D expense. In our consolidated results, we eliminate this sublicense revenue and expense. Any cash Akcea receives is included in our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018 and 2017, we earned the following revenue from our relationship with Novartis (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our &lt;/font&gt;consolidated balance sheet at &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 31, 2018 and 2017 included deferred revenue of $28.8 million and $70.7 million, respectively, related to our relationship with Novartis.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;External Project Funding&lt;/div&gt;&lt;/div&gt;&lt;div style="background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are pursuing discovery and development projects that provide us with new therapeutic applications for antisense medicines. These programs represent opportunities for us and our technology. In some cases, we have funded these studies through support from our partners or disease advocacy groups and foundations. Our External Project Funding partners include the following:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;CHDI Foundation&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;- &lt;/font&gt;Through our development collaboration, CHDI provided financial and scientific support to our Huntington&amp;#8217;s disease drug discovery program. W&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;e have reimbursed CHDI for its support of our Huntington&amp;#8217;s disease program out of the payments we receive from Roche.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Cystic Fibrosis Foundation&lt;/font&gt;- We received upfront funding from the Cystic Fibrosis Foundation to discover and advance a medicine for the treatment of cystic fibrosis. In exchange for this funding, we are obligated to pay the Cystic Fibrosis Foundation up to $18 million upon achieving specific regulatory and sales events if we advance a medicine under our collaboration.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;The Ludwig Institute; Center for Neurological Studies- &lt;/font&gt;We have a collaboration with the Ludwig Institute, the Center for Neurological Studies and researchers to discover and develop antisense medicines for ALS and other neurodegenerative diseases. Under this agreement, we agreed to pay the Ludwig Institute and the Center for Neurological Studies modest milestone payments and royalties on any antisense medicines resulting from the collaboration.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;In-Licensing Agreements&lt;/div&gt;&lt;/div&gt;&lt;div style="background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our in-licensing arrangements include:&lt;/font&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;University of Massachusetts- &lt;/font&gt;We have a license agreement with the University of Massachusetts under which we acquired an exclusive license to the University of Massachusetts&amp;#8217; patent rights related to SPINRAZA. We paid the University of Massachusetts nominal amounts for license fees and milestone payments we received. We also pay a low single digit royalty on net sales of SPINRAZA.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Cold Spring Harbor Laboratory-&lt;/font&gt; We have a collaboration and license agreement with the Cold Spring Harbor Laboratory under which we acquired an exclusive license to the Cold Spring Harbor Laboratory&amp;#8217;s patent rights related to SPINRAZA. We paid Cold Spring Harbor Laboratory nominal amounts for license fees and milestone payments we received in 2017 and a low single digit royalty on net sales of SPINRAZA. Additionally, we owe a low single digit royalty on future sales of SPINRAZA.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:CollaborativeArrangementDisclosureTextBlock>
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  <!--Contractual Obligation, Fiscal Year Maturity Schedule [Table Text Block]-->
  <us-gaap:ContractualObligationFiscalYearMaturityScheduleTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Annual debt and other obligation maturities, including fixed and determinable interest, at December 31, 2018 are as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2019&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;22,067&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2020&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;9,330&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2021&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;694,774&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2022&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,809&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2023&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3,494&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Thereafter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;68,108&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Subtotal&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;800,582&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Less: current portion&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,890&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Less: fixed and determinable interest&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(41,837&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Less: unamortized portion of debt discount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(111,426&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Plus: Deferred rent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4,960&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;639,389&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ContractualObligationFiscalYearMaturityScheduleTableTextBlock>
  <!--Convertible Notes-->
  <us-gaap:ConvertibleDebtTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At December 31, 2018, we had a nominal amount of our 2&amp;#190; percent convertible senior notes outstanding. At December 31, 2018, we had the following 1 percent convertible senior notes outstanding (amounts in millions except price per share data):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: top; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;1 Percent&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Convertible Senior Notes&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Outstanding balance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;685.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Original issue date ($500 million of principal)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: top; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;November 2014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Additional issue date ($185.5 million of principal)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: top; background-color: #CCEEFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Maturity date&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: top; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;November 2021&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: top; background-color: #CCEEFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1 percent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Conversion price per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66.81&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -12.05pt; margin-left: 12.05pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total shares of common stock subject to conversion&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We account for our convertible notes using an accounting standard that requires us to assign a value to our convertible debt equal to the estimated fair value of similar debt instruments without the conversion feature and to record the remaining portion in equity. As a result, we recorded our convertible notes at a discount, which we are amortizing as additional non-cash interest expense over the expected life of the respective debt. We determined our nonconvertible debt borrowing rate using a combination of the present value of the debt&amp;#8217;s cash flows and a Black-Scholes valuation model. The following table summarizes the nonconvertible borrowing rate, effective interest rate and amortization period of our debt discount for our convertible notes:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td style="width: 41.98%; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td style="width: 27.8%; vertical-align: bottom; border-bottom: #000000 2px solid;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;1 Percent&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Convertible Senior Notes&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Issued in November 2014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 2.91%; vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td style="width: 27.32%; vertical-align: bottom; border-bottom: #000000 2px solid;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;1 Percent&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Convertible Senior Notes&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Issued in December 2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td style="width: 41.98%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Nonconvertible debt borrowing rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 27.8%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7.4 percent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 2.91%; vertical-align: top; background-color: rgb(204, 238, 255);"&gt;&amp;#160;&lt;/td&gt;&lt;td style="width: 27.32%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.8 percent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td style="width: 41.98%; vertical-align: bottom; background-color: rgb(255, 255, 255);"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effective interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 27.8%; vertical-align: bottom; background-color: rgb(255, 255, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7.8 percent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 2.91%; vertical-align: top; background-color: rgb(255, 255, 255);"&gt;&amp;#160;&lt;/td&gt;&lt;td style="width: 27.32%; vertical-align: bottom; background-color: rgb(255, 255, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7.2 percent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td style="width: 41.98%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Amortization period of debt discount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 27.8%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 2.91%; vertical-align: top; background-color: rgb(204, 238, 255);"&gt;&amp;#160;&lt;/td&gt;&lt;td style="width: 27.32%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5 years&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes information about the equity and liability components of our outstanding 1 percent convertible notes (in thousands). We measured the fair values of the convertible notes outstanding based on quoted market prices, which is a Level 2 measurement:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center; text-indent: 16pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Fair value of outstanding notes&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;724,966&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;727,420&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Principal amount of convertible notes outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;685,450&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;685,450&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Unamortized portion of debt discount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;110,817&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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Long-Term Obligations and Commitments&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The carrying value of our long-term obligations was as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1 percent convertible senior notes&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Long-term mortgage debt&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;59,842&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;59,771&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Principal balance of fixed rate note with Morgan Stanley (1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;12,500&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;12,500&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Leases and other obligations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,163&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,095&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;646,720&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;607,477&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Less: current portion&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(13,749&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,621&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total Long-Term Obligations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;632,971&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;605,856&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our $12.5 million fixed rate note with Morgan Stanley is included in our current portion of long-term obligations on our consolidated balance sheet at December 31, 2018.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Convertible Notes&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In November 2014, we completed a $500 million offering of convertible senior notes, which mature in 2021 and bear interest at 1 percent. We raised $487 million of proceeds, net of issuance costs. We used a substantial portion of the net proceeds from the issuance of the 1 percent convertible senior notes to repurchase $140 million in principal of our 2&amp;#190; percent convertible senior notes at a price of $441.9 million, including accrued interest. As a result, the new principal balance of the 2&amp;#190; percent notes was $61.2 million.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In December 2016, we issued an additional $185.5 million of 1 percent convertible senior notes in exchange for the redemption of $61.1 million of our 2&amp;#190; percent convertible senior notes. As a result of the debt exchange we completed in December 2016, we recorded a $4.0 million non-cash loss on early retirement of debt, reflecting the early retirement of the majority of our remaining 2&amp;#190;&amp;#160;percent convertible notes in December 2016.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;At December 31, 2018, we had a nominal amount of our 2&amp;#190; percent convertible senior notes outstanding. At December 31, 2018, we had the following 1 percent convertible senior notes outstanding (amounts in millions except price per share data):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: top; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;1 Percent&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Convertible Senior Notes&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Outstanding balance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;685.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Original issue date ($500 million of principal)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: top; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;November 2014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Additional issue date ($185.5 million of principal)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: top; background-color: #CCEEFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Maturity date&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: top; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;November 2021&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: top; background-color: #CCEEFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1 percent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Conversion price per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66.81&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -12.05pt; margin-left: 12.05pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total shares of common stock subject to conversion&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest is payable semi-annually in arrears on May 15 and November 15 of each year for the 1 percent notes. The 1 percent notes are convertible at the option of the note holders prior to July&amp;#160;1, 2021 only under certain conditions. On or after July&amp;#160;1, 2021, the notes are initially convertible into approximately 10.3 million shares of common stock at a conversion price of approximately $66.81 per share. We will 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 1 percent notes prior to maturity, and no sinking fund is provided for them. If we undergo a fundamental change, holders may require us to purchase for cash all or any portion of their 1 percent notes at a purchase price equal to 100 percent of the principal amount of the notes to be purchased, plus accrued and unpaid interest to, but excluding, the fundamental change purchase date.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We account for our convertible notes using an accounting standard that requires us to assign a value to our convertible debt equal to the estimated fair value of similar debt instruments without the conversion feature and to record the remaining portion in equity. As a result, we recorded our convertible notes at a discount, which we are amortizing as additional non-cash interest expense over the expected life of the respective debt. We determined our nonconvertible debt borrowing rate using a combination of the present value of the debt&amp;#8217;s cash flows and a Black-Scholes valuation model. The following table summarizes the nonconvertible borrowing rate, effective interest rate and amortization period of our debt discount for our convertible notes:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td style="width: 41.98%; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td style="width: 27.8%; vertical-align: bottom; border-bottom: #000000 2px solid;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;1 Percent&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Convertible Senior Notes&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Issued in November 2014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 2.91%; vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td style="width: 27.32%; vertical-align: bottom; border-bottom: #000000 2px solid;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;1 Percent&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Convertible Senior Notes&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Issued in December 2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td style="width: 41.98%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Nonconvertible debt borrowing rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 27.8%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7.4 percent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 2.91%; vertical-align: top; background-color: rgb(204, 238, 255);"&gt;&amp;#160;&lt;/td&gt;&lt;td style="width: 27.32%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.8 percent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td style="width: 41.98%; vertical-align: bottom; background-color: rgb(255, 255, 255);"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effective interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 27.8%; vertical-align: bottom; background-color: rgb(255, 255, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7.8 percent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 2.91%; vertical-align: top; background-color: rgb(255, 255, 255);"&gt;&amp;#160;&lt;/td&gt;&lt;td style="width: 27.32%; vertical-align: bottom; background-color: rgb(255, 255, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7.2 percent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td style="width: 41.98%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Amortization period of debt discount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 27.8%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: 2.91%; vertical-align: top; background-color: rgb(204, 238, 255);"&gt;&amp;#160;&lt;/td&gt;&lt;td style="width: 27.32%; vertical-align: bottom; background-color: rgb(204, 238, 255);"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5 years&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Interest expense for the years ended December 31, 2018, 2017 and 2016 included $35.2 million, $32.5 million and $25.1 million, respectively, of non-cash interest expense related to the amortization of the debt discount and debt issuance costs for our convertible notes.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes information about the equity and liability components of our outstanding 1 percent convertible notes (in thousands). We measured the fair values of the convertible notes outstanding based on quoted market prices, which is a Level 2 measurement:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center; text-indent: 16pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Fair value of outstanding notes&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;724,966&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;727,420&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Principal amount of convertible notes outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;685,450&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;685,450&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Unamortized portion of debt discount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;110,817&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;144,112&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Long-term debt&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;568,215&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;533,111&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Carrying value of equity component&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;219,011&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;219,011&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Financing Arrangements&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Line of Credit Arrangement&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In June 2015, we entered into a five-year revolving line of credit agreement with Morgan Stanley Private Bank, National Association, or Morgan Stanley. We amended the credit agreement in February 2016 to increase the amount available for us to borrow. Under the amended credit agreement, we can borrow up to a maximum of $30 million of revolving credit for general working capital purposes. Under the credit agreement interest is payable monthly in arrears on the outstanding principal at a borrowing rate based on our option of:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&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%;"&gt;&lt;tr&gt;&lt;td style="width: 58.5pt; vertical-align: top; align: right;"&gt;&lt;div style="text-align: left; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(i)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;a floating rate equal to the one-month London Interbank Offered Rate, or LIBOR, in effect plus 1.25 percent per annum;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&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%;"&gt;&lt;tr&gt;&lt;td style="width: 58.5pt; vertical-align: top; align: right;"&gt;&lt;div style="text-align: left; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(ii)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;a fixed rate equal to LIBOR plus 1.25 percent for a period of one, two, three, four, six, or twelve months as elected by us; or&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&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%;"&gt;&lt;tr&gt;&lt;td style="width: 58.5pt; vertical-align: top; align: right;"&gt;&lt;div style="text-align: left; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(iii)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;a fixed rate equal to the LIBOR swap rate during the period of the loan.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Additionally, after June 1, 2016, we pay 0.25 percent per annum, payable quarterly in arrears, for any amount unused under the credit facility. As of December 31, 2018, we had $12.5 million in outstanding borrowings under the credit facility with a 2.31 percent fixed interest rate and a maturity date of September 2019, which we used to fund our capital equipment needs.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The credit agreement includes customary affirmative and negative covenants and restrictions. We are in compliance with all covenants of the credit agreement.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Research and Development and Manufacturing Facilities&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In July 2017, we purchased the building that houses our primary R&amp;amp;D facility for $79.4 million. As a result of the purchase, we extinguished the financing liability we had previously recorded on our balance sheet. The difference between the purchase price of the facility and the carrying value of our financing liability at the time of the purchase was $7.7 million. We recognized this amount as a non-cash loss on extinguishment of financing liability for leased facility in our consolidated results of operations in the third quarter of 2017.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We also purchased our manufacturing facility in July 2017 for $14.0 million. We previously accounted for the lease on this facility as an operating lease. We capitalized the purchase price of the building as a fixed asset in the third quarter of 2017.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We financed the purchase of our primary R&amp;amp;D facility and our manufacturing facility, with mortgage debt of $51.3 million and $9.1 million, respectively. Our primary R&amp;amp;D facility mortgage has an interest rate of 3.88 percent. Our manufacturing facility mortgage has an interest rate of 4.20 percent. During the first five years of both mortgages we are only required to make interest payments. Both mortgages mature in August 2027.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Maturity Schedules&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Annual debt and other obligation maturities, including fixed and determinable interest, at December 31, 2018 are as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2019&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;22,067&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2020&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;9,330&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2021&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;694,774&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2022&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,809&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2023&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3,494&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Thereafter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;68,108&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Subtotal&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;800,582&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Less: current portion&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,890&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Less: fixed and determinable interest&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(41,837&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Less: unamortized portion of debt discount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(111,426&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Plus: Deferred rent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4,960&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;639,389&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Operating Leases&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Ionis Leases&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We lease a facility adjacent to our manufacturing facility that has laboratory and office space that we use to support our manufacturing facility. We lease this space under a non-cancelable operating lease with an initial term ending in June 2021 and an option to extend the lease for up to two five-year periods.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Additionally, we lease office space that we sublease to Akcea. We lease this space under a non-cancelable operating lease with an initial term ending in June 2023 and an option to extend the lease for one five-year period. The sublease with Akcea is eliminated in our consolidated financial statements. We also lease office equipment under non-cancelable operating leases with terms through January 2021.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Akcea Lease&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;On April 5, 2018, Akcea entered into an operating lease agreement for office space located in Boston, Massachusetts for its new corporate headquarters. The lease commencement date was August 15, 2018 and Akcea took occupancy in September 2018. Akcea is leasing this space under a non-cancelable operating lease with an initial term ending after 123 months and an option to extend the lease for an additional five-year term. Under the lease agreement, Akcea received a three-month free rent period, which commenced on August 15, 2018, and a tenant improvement allowance up to $3.8 million. Akcea provided the lessor with a letter of credit to secure its obligations under the lease in the initial amount of $2.4 million, to be reduced to $1.8 million on the third anniversary of the rent commencement date and to $1.2 million on the fifth anniversary of the rent commencement date if Akcea meets certain conditions set forth in the lease at each such time. The letter of credit amount is included in deposits and other assets in our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Annual future minimum payments under our operating leases as of December 31, 2018 are as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Operating&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Leases&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2019&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3,129&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2020&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3,008&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2021&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,725&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2022&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,539&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2023&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,505&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Thereafter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11,862&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total minimum payments&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;25,768&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Rent expense was $2.6 million, $1.7 million and $2.0 million for the years ended December 31, 2018, 2017 and 2016. We recognized rent expense on a straight line basis over the lease term for the lease on our building adjacent to our manufacturing facility, the office building that Akcea subleases and Akcea&amp;#8217;s office space, which resulted in a deferred rent balance of $5.0 million and $0.1 million at December 31, 2018 and 2017, respectively.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:DebtAndCapitalLeasesDisclosuresTextBlock>
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  <us-gaap:DebtPolicyTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Convertible Debt&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We account for convertible debt instruments, including our 1 percent and 2&amp;#190; percent notes that may be settled in cash upon conversion (including partial cash settlement) by separating the liability and equity components of the instruments in a manner that reflects our nonconvertible debt borrowing rate. We determine the carrying amount of the liability component by measuring the fair value of similar debt instruments that do not have the conversion feature. If no similar debt instrument exists, we estimate fair value by using assumptions that market participants would use in pricing a debt instrument, including market interest rates, credit standing, yield curves and volatilities. We use accounting estimates and assumptions when we determine the fair value of the debt component. These estimates and assumptions we use are judgmental in nature and could have a significant impact on the determination of the debt component, and the associated non-cash interest expense.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We assigned a value to the debt component of our convertible notes equal to the estimated fair value of similar debt instruments without the conversion feature, which resulted in us recording our debt at a discount. We are amortizing our debt issuance costs and debt discount over the life of the convertible notes as additional non-cash interest expense utilizing the effective interest method. For additional information, see Note 3, &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Long-Term Obligations and Commitments&lt;/font&gt;.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:DebtPolicyTextBlock>
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  <!--Deferred Tax Assets, Net-->
  <us-gaap:DeferredTaxAssetsLiabilitiesNet contextRef="c20171231" unitRef="U001" decimals="-3">0</us-gaap:DeferredTaxAssetsLiabilitiesNet>
  <!--Deferred Tax Assets, Gross-->
  <us-gaap:DeferredTaxAssetsGross contextRef="c20171231" unitRef="U001" decimals="-3">501093000</us-gaap:DeferredTaxAssetsGross>
  <!--Deferred Tax Assets, Gross-->
  <us-gaap:DeferredTaxAssetsGross contextRef="c20181231" unitRef="U001" decimals="-3">549059000</us-gaap:DeferredTaxAssetsGross>
  <!--Deferred Tax Assets, Other-->
  <us-gaap:DeferredTaxAssetsOther contextRef="c20181231" unitRef="U001" decimals="-3">8275000</us-gaap:DeferredTaxAssetsOther>
  <!--Deferred Tax Assets, Other-->
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  <!--Deferred Tax Assets, Deferred Income-->
  <us-gaap:DeferredTaxAssetsDeferredIncome contextRef="c20171231" unitRef="U001" decimals="-3">54302000</us-gaap:DeferredTaxAssetsDeferredIncome>
  <!--Deferred Tax Assets, Deferred Income-->
  <us-gaap:DeferredTaxAssetsDeferredIncome contextRef="c20181231" unitRef="U001" decimals="-3">27381000</us-gaap:DeferredTaxAssetsDeferredIncome>
  <!--Deferred Tax Assets, Operating Loss Carryforwards-->
  <us-gaap:DeferredTaxAssetsOperatingLossCarryforwards contextRef="c20181231" unitRef="U001" decimals="-3">89717000</us-gaap:DeferredTaxAssetsOperatingLossCarryforwards>
  <!--Deferred Tax Assets, Operating Loss Carryforwards-->
  <us-gaap:DeferredTaxAssetsOperatingLossCarryforwards contextRef="c20171231" unitRef="U001" decimals="-3">153575000</us-gaap:DeferredTaxAssetsOperatingLossCarryforwards>
  <!--Deferred Tax Assets, Tax Deferred Expense, Compensation and Benefits, Share-based Compensation Cost-->
  <us-gaap:DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost contextRef="c20181231" unitRef="U001" decimals="-3">61027000</us-gaap:DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost>
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  <us-gaap:DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost contextRef="c20171231" unitRef="U001" decimals="-3">40090000</us-gaap:DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost>
  <!--Deferred Tax Assets, Tax Credit Carryforwards, Research-->
  <us-gaap:DeferredTaxAssetsTaxCreditCarryforwardsResearch contextRef="c20181231" unitRef="U001" decimals="-3">313652000</us-gaap:DeferredTaxAssetsTaxCreditCarryforwardsResearch>
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  <us-gaap:DeferredTaxAssetsTaxCreditCarryforwardsResearch contextRef="c20171231" unitRef="U001" decimals="-3">240290000</us-gaap:DeferredTaxAssetsTaxCreditCarryforwardsResearch>
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  <us-gaap:DeferredTaxAssetsValuationAllowance contextRef="c20181231" unitRef="U001" decimals="-3">234245000</us-gaap:DeferredTaxAssetsValuationAllowance>
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  <us-gaap:DeferredTaxAssetsValuationAllowance contextRef="c20171231" unitRef="U001" decimals="-3">468702000</us-gaap:DeferredTaxAssetsValuationAllowance>
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  <us-gaap:DeferredTaxLiabilitiesFinancingArrangements contextRef="c20181231" unitRef="U001" decimals="-3">24018000</us-gaap:DeferredTaxLiabilitiesFinancingArrangements>
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  <us-gaap:DeferredTaxLiabilitiesFinancingArrangements contextRef="c20171231" unitRef="U001" decimals="-3">32391000</us-gaap:DeferredTaxLiabilitiesFinancingArrangements>
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  <!--Defined Contribution Plan, Cost-->
  <us-gaap:DefinedContributionPlanCostRecognized contextRef="c20180101to20181231" unitRef="U001" decimals="-5">5700000</us-gaap:DefinedContributionPlanCostRecognized>
  <!--Defined Contribution Plan, Cost-->
  <us-gaap:DefinedContributionPlanCostRecognized contextRef="c20160101to20161231" unitRef="U001" decimals="-5">1700000</us-gaap:DefinedContributionPlanCostRecognized>
  <!--Depreciation-->
  <us-gaap:Depreciation contextRef="c20160101to20161231" unitRef="U001" decimals="-3">7481000</us-gaap:Depreciation>
  <!--Depreciation-->
  <us-gaap:Depreciation contextRef="c20180101to20181231" unitRef="U001" decimals="-3">10706000</us-gaap:Depreciation>
  <!--Depreciation-->
  <us-gaap:Depreciation contextRef="c20170101to20171231" unitRef="U001" decimals="-3">6708000</us-gaap:Depreciation>
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  <!--Basic net income (loss) per share (in dollars per share)-->
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  <!--Basic net income (loss) per share (in dollars per share)-->
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  <!--Basic net income (loss) per share (in dollars per share)-->
  <us-gaap:EarningsPerShareBasic contextRef="c20181001to20181231" unitRef="U004" decimals="2" id="Item-35">2.32</us-gaap:EarningsPerShareBasic>
  <!--Basic net income (loss) per share (in dollars per share)-Common Stock [Member]-Akcea Therapeutics, Inc. [Member]-->
  <us-gaap:EarningsPerShareBasic contextRef="c20171001to20171231_OwnershipAxis_AkceaTherapeuticsIncMember_StatementClassOfStockAxis_CommonStockMember" unitRef="U004" decimals="2">-0.30</us-gaap:EarningsPerShareBasic>
  <!--Basic net income (loss) per share (in dollars per share)-Common Stock [Member]-Akcea Therapeutics, Inc. [Member]-->
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  <!--Basic net income (loss) per share (in dollars per share)-Common Stock [Member]-Akcea Therapeutics, Inc. [Member]-->
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  <!--Basic net income (loss) per share (in dollars per share)-Common Stock [Member]-Akcea Therapeutics, Inc. [Member]-->
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  <!--Basic net income (loss) per share (in dollars per share)-->
  <us-gaap:EarningsPerShareBasic contextRef="c20170101to20170331" unitRef="U004" decimals="2" id="Item-36">0.07</us-gaap:EarningsPerShareBasic>
  <!--Basic net income (loss) per share (in dollars per share)-->
  <us-gaap:EarningsPerShareBasic contextRef="c20180401to20180630" unitRef="U004" decimals="2" id="Item-37">-0.29</us-gaap:EarningsPerShareBasic>
  <!--Basic net income (loss) per share (in dollars per share)-->
  <us-gaap:EarningsPerShareBasic contextRef="c20170401to20170630" unitRef="U004" decimals="2" id="Item-38">-0.02</us-gaap:EarningsPerShareBasic>
  <!--Basic net income (loss) per share (in dollars per share)-->
  <us-gaap:EarningsPerShareBasic contextRef="c20180701to20180930" unitRef="U004" decimals="2" id="Item-39">-0.03</us-gaap:EarningsPerShareBasic>
  <!--Basic net income (loss) per share (in dollars per share)-Akcea Therapeutics, Inc. [Member]-Convertible Preferred Stock [Member]-->
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  <!--Basic net income (loss) per share (in dollars per share)-->
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  <!--Basic net income (loss) per share (in dollars per share)-->
  <us-gaap:EarningsPerShareBasic contextRef="c20170701to20170930" unitRef="U004" decimals="2" id="Item-41">-0.02</us-gaap:EarningsPerShareBasic>
  <!--Basic and Diluted Net Income (Loss) per Share-->
  <us-gaap:EarningsPerSharePolicyTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic and Diluted Net Income (Loss) per Share&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Basic net income (loss) per share&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The calculation of total net income (loss) attributable to our common stockholders for 2018 and 2017 considered our net income for Ionis on a stand-alone basis plus our share of Akcea&amp;#8217;s net loss for the period. During 2016, we owned 100 percent of Akcea. To calculate the portion of Akcea&amp;#8217;s net loss attributable to our ownership for 2018 and 2017, we multiplied Akcea&amp;#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our&amp;#160;total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for 2018 and 2017.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our basic net income per share for &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2018&lt;/font&gt;, was calculated as follows (in thousands, except per share amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Income (Loss)&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Portion of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;59,812&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2.74&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(163,938&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(163,938&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;440,806&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;276,868&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;132,320&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.09&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Prior to Akcea&amp;#8217;s IPO in July 2017, we owned Akcea series A convertible preferred stock, which included a six percent cumulative dividend. Upon completion of Akcea&amp;#8217;s IPO in July 2017, our preferred stock was converted into common stock on a 1:1 basis. The preferred stock dividend was not paid at the IPO because the IPO was not a liquidation event or a change in control. During 2017, Akcea used a two-class method to compute its net income (loss) per share because it had both common and preferred shares outstanding during the periods. The two-class method required Akcea to calculate its net income (loss) per share&amp;#160;for each class of stock by dividing total distributable losses applicable to preferred and common stock, including the&amp;#160;six percent&amp;#160;cumulative dividend contractually due to series A convertible preferred shareholders, by the weighted-average of preferred and common shares outstanding during the requisite period. Since Akcea used the two-class method, accounting rules required us to include our portion of Akcea&amp;#8217;s net income (loss) per share for both Akcea&amp;#8217;s common and preferred shares that we owned in our calculation of basic and diluted net income (loss) per share for year ended December 31, 2017.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our basic net income per share for 2017 as follows (in thousands, except per share amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Loss&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Portion of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;20,669&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3.08&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(63,638&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Preferred shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;15,748&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1.80&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(28,346&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(91,984&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;110,776&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,792&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Dilutive net income (loss per share)&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For 2018 and 2017, we had net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our diluted net income per share for 2018 as follows &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(in thousands except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Income&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Numerator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Denominator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per-Share&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;276,868&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;132,320&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.09&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effect of dilutive securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon exercise of stock options&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,216&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon restricted stock award issuance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;514&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our ESPP&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income available to Ionis common stockholders, plus assumed conversions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;276,868&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;134,056&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We calculated our diluted net income per share for 2017 as follows &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(in thousands except per share amounts):&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Income&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Numerator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Denominator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per-Share&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,792&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effect of dilutive securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon exercise of stock options&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,619&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon restricted stock award issuance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;459&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our ESPP&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income available to Ionis common stockholders, plus assumed conversions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,792&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;126,098&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For 2018 and 2017, the calculation excluded our convertible notes because the effect on diluted earnings per share was anti-dilutive.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For 2016, 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;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1 percent convertible senior notes;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2&amp;#190; percent convertible senior notes;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dilutive stock options;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Unvested restricted stock units; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Employee Stock Purchase Plan, or ESPP.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:EarningsPerSharePolicyTextBlock>
  <!--Earnings Per Share, Basic and Diluted-->
  <us-gaap:EarningsPerShareBasicAndDiluted contextRef="c20160101to20161231" unitRef="U004" decimals="2">-0.50</us-gaap:EarningsPerShareBasicAndDiluted>
  <!--Earnings Per Share, Basic and Diluted-Topic 606 Adjustment [Member]-Topic 606 [Member]-->
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  <!--Effective Income Tax Rate Reconciliation, Tax Credit, Percent-->
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  <!--Effective Income Tax Rate Reconciliation, Tax Credit, Percent-->
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  <!--Effective Income Tax Rate Reconciliation, Prior Year Income Taxes, Percent-->
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  <!--Effective Income Tax Rate Reconciliation, Prior Year Income Taxes, Percent-->
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  <!--Effective Income Tax Rate Reconciliation, Percent-->
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  <!--Effective Income Tax Rate Reconciliation, Percent-->
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  <!--Effective Income Tax Rate Reconciliation, Percent-->
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  <!--Fair Value Measurement, Policy [Policy Text Block]-->
  <us-gaap:FairValueMeasurementPolicyPolicyTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value Measurements&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity securities in publicly-held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify the majority of our securities as Level 2. We obtain the fair value of our Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and comparing that fair value to the fair value based on observable market prices. During 2018 and 2017, there were no transfers between our Level 1 and Level 2 investments. When we recognize transfers between levels of the fair value hierarchy, we recognize the transfer on the date the event or change in circumstances that caused the transfer occurs.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following tables present the major security types we held at December 31, 2018 and 2017 that are regularly measured and carried at fair value. At December 31, 2018, our ProQR investment was &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;subject to trading restrictions through the fourth quarter of 2019, as a result we&lt;/font&gt; included a lack of marketability discount in valuing this investment, which is a Level 3 input. At December 31, 2017, we did not have any financial instruments that we valued using Level 3 inputs. The tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities&amp;#8217; fair value (in thousands):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quoted Prices in&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Active Markets&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Significant Other&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Observable Inputs&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; 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text-align: right; width: 9%; background-color: rgb(255, 255, 255); border-bottom: 2px solid rgb(0, 0, 0);"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: 2px solid rgb(0, 0, 0); background-color: rgb(255, 255, 255);"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,017,298&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;406,435&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,609,514&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,349&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;At&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quoted Prices in&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Active Markets&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Significant Other&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Observable Inputs&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash equivalents (1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;86,262&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;86,262&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Corporate debt securities (6)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;647,461&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;647,461&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by U.S. government agencies (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;136,325&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;136,325&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by the U.S. Treasury (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;30,818&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;30,818&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (7)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;93,932&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;93,932&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;994,798&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;117,080&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;877,718&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div style="text-align: justify; text-indent: 500.1pt;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Included in cash and cash equivalents on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$50.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$14.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Included in other current assets on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(6)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$11.9 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(7)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$3.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Novartis Future Stock Purchase&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In January 2017, we and Akcea entered into a SPA with Novartis. As part of the SPA, Novartis was required to purchase $50 million of Akcea&amp;#8217;s common stock at the IPO price or our common stock at a premium if an IPO did not occur by April 2018. Therefore, at the inception of the SPA, we recorded a $5.0 million asset representing the fair value of the potential future premium we could have received if Novartis purchased our common stock. We determined the fair value of the future premium by calculating the value based on the stated premium in the SPA and estimating the probability of an Akcea IPO. We also included a &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;lack of marketability discount when we determined the fair value of the premium because we would have issued unregistered shares to Novartis if they had purchased our common stock. We measured this asset using Level 3 inputs and recorded it in other assets on our consolidated balance sheet. Because Akcea completed its IPO before April 2018, Novartis will not purchase additional shares of Ionis stock. Therefore, this asset no longer had any value and we wrote-off the remaining balance to other expenses on our third quarter 2017 consolidated statement of operations.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following is a reconciliation of the potential premium we would have received if Akcea had not completed its IPO, measured at fair value on a recurring basis using significant unobservable inputs (Level 3) for 2017 (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Beginning balance of Level 3 instruments&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Value of the potential premium we will receive from Novartis at inception of the SPA (January 2017)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5,035&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Write-off of premium to other expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,035&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ending balance of Level 3 instruments&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:FairValueMeasurementPolicyPolicyTextBlock>
  <!--Fair Value, Measurement with Unobservable Inputs Reconciliation, Recurring Basis, Asset, Gain (Loss) Included in Earnings-Potential Future Premium [Member]-->
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  <!--Fair Value, Measurement with Unobservable Inputs Reconciliation, Recurring Basis, Asset Transfers Into Level 3-Potential Future Premium [Member]-->
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  <!--Fair Value of Financial Instruments, Policy [Policy Text Block]-->
  <us-gaap:FairValueOfFinancialInstrumentsPolicy contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value of Financial Instruments&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable, accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:FairValueOfFinancialInstrumentsPolicy>
  <!--Fair Value, Assets Measured on Recurring Basis [Table Text Block]-->
  <us-gaap:FairValueAssetsMeasuredOnRecurringBasisTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quoted Prices in&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Active Markets&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;276,612&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by the U.S. Treasury (4)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;260,154&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;79,942&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Investment in ProQR Therapeutics N.V. (5)&lt;/font&gt;&lt;/div&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: rgb(255, 255, 255); border-bottom: 2px solid rgb(0, 0, 0);"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: rgb(255, 255, 255); border-bottom: 2px solid rgb(0, 0, 0);"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,349&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; 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font-family: 'Times New Roman', Times, serif;"&gt;406,435&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,609,514&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,349&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;At&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quoted Prices in&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Active Markets&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Significant Other&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Observable Inputs&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash equivalents (1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;86,262&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;86,262&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Corporate debt securities (6)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;647,461&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;647,461&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by U.S. government agencies (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by the U.S. Treasury (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;30,818&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;30,818&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (7)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;93,932&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;93,932&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;994,798&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;117,080&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;877,718&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div style="text-align: justify; text-indent: 500.1pt;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Included in cash and cash equivalents on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$50.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$14.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Included in other current assets on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(6)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$11.9 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(7)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$3.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:FairValueAssetsMeasuredOnRecurringBasisTextBlock>
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border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Beginning balance of Level 3 instruments&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Value of the potential premium we will receive from Novartis at inception of the SPA (January 2017)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5,035&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Write-off of premium to other expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,035&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ending balance of Level 3 instruments&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationTextBlock>
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  <us-gaap:FiniteLivedIntangibleAssetsGross contextRef="c20181231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">32700000</us-gaap:FiniteLivedIntangibleAssetsGross>
  <!--Finite-Lived Intangible Assets, Gross-Patents [Member]-->
  <us-gaap:FiniteLivedIntangibleAssetsGross contextRef="c20171231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">30800000</us-gaap:FiniteLivedIntangibleAssetsGross>
  <!--Finite-Lived Intangible Assets, Amortization Expense, Year Three-Patents [Member]-->
  <us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseYearThree contextRef="c20181231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">1500000</us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseYearThree>
  <!--Finite-Lived Intangible Asset, Useful Life-Patents [Member]-->
  <us-gaap:FiniteLivedIntangibleAssetUsefulLife contextRef="c20180101to20181231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember">P10Y1M6D</us-gaap:FiniteLivedIntangibleAssetUsefulLife>
  <!--Finite-Lived Intangible Assets, Amortization Expense, Year Four-Patents [Member]-->
  <us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseYearFour contextRef="c20181231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">1400000</us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseYearFour>
  <!--Finite-Lived Intangible Assets, Accumulated Amortization-Patents [Member]-->
  <us-gaap:FiniteLivedIntangibleAssetsAccumulatedAmortization contextRef="c20181231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">8700000</us-gaap:FiniteLivedIntangibleAssetsAccumulatedAmortization>
  <!--Finite-Lived Intangible Assets, Accumulated Amortization-Patents [Member]-->
  <us-gaap:FiniteLivedIntangibleAssetsAccumulatedAmortization contextRef="c20171231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">8800000</us-gaap:FiniteLivedIntangibleAssetsAccumulatedAmortization>
  <!--Finite-Lived Intangible Assets, Amortization Expense, Next Twelve Months-Patents [Member]-->
  <us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths contextRef="c20181231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">1700000</us-gaap:FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths>
  <!--Gain on Sale of Investments-->
  <us-gaap:GainOnSaleOfInvestments contextRef="c20160101to20161231" unitRef="U001" decimals="-3">0</us-gaap:GainOnSaleOfInvestments>
  <!--Gain on Sale of Investments-->
  <us-gaap:GainOnSaleOfInvestments contextRef="c20170101to20171231" unitRef="U001" decimals="-3">374000</us-gaap:GainOnSaleOfInvestments>
  <!--Gain on Sale of Investments-->
  <us-gaap:GainOnSaleOfInvestments contextRef="c20180101to20181231" unitRef="U001" decimals="-3">0</us-gaap:GainOnSaleOfInvestments>
  <!--Gain (Loss) on Extinguishment of Debt-->
  <us-gaap:GainsLossesOnExtinguishmentOfDebt contextRef="c20180101to20181231" unitRef="U001" decimals="-3">0</us-gaap:GainsLossesOnExtinguishmentOfDebt>
  <!--Gain (Loss) on Extinguishment of Debt-->
  <us-gaap:GainsLossesOnExtinguishmentOfDebt contextRef="c20160101to20161231" unitRef="U001" decimals="-3">-3983000</us-gaap:GainsLossesOnExtinguishmentOfDebt>
  <!--Gain (Loss) on Extinguishment of Debt-->
  <us-gaap:GainsLossesOnExtinguishmentOfDebt contextRef="c20170101to20171231" unitRef="U001" decimals="-3">0</us-gaap:GainsLossesOnExtinguishmentOfDebt>
  <!--Gain (Loss) on Extinguishment of Debt-Convertible Senior Notes 2.75 Percent [Member]-->
  <us-gaap:GainsLossesOnExtinguishmentOfDebt contextRef="c20161201to20161231_DebtInstrumentAxis_ConvertibleSeniorNotes275PercentMember" unitRef="U001" decimals="-3">3983000</us-gaap:GainsLossesOnExtinguishmentOfDebt>
  <!--Impairment or Disposal of Long-Lived Assets, Including Intangible Assets, Policy [Policy Text Block]-->
  <us-gaap:ImpairmentOrDisposalOfLongLivedAssetsIncludingIntangibleAssetsPolicyPolicyTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Long-Lived Assets&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. We recorded charges of $0.8 million, $0.8 million and $2.3 million for the years ended December 31, 2018, 2017 and 2016, respectively, related primarily to the write-down of intangible assets.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ImpairmentOrDisposalOfLongLivedAssetsIncludingIntangibleAssetsPolicyPolicyTextBlock>
  <!--Impairment of Intangible Assets, Finite-lived-Patents [Member]-->
  <us-gaap:ImpairmentOfIntangibleAssetsFinitelived contextRef="c20160101to20161231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">2300000</us-gaap:ImpairmentOfIntangibleAssetsFinitelived>
  <!--Impairment of Intangible Assets, Finite-lived-Patents [Member]-->
  <us-gaap:ImpairmentOfIntangibleAssetsFinitelived contextRef="c20180101to20181231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">800000</us-gaap:ImpairmentOfIntangibleAssetsFinitelived>
  <!--Impairment of Intangible Assets, Finite-lived-Patents [Member]-->
  <us-gaap:ImpairmentOfIntangibleAssetsFinitelived contextRef="c20170101to20171231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">400000</us-gaap:ImpairmentOfIntangibleAssetsFinitelived>
  <!--Income (Loss) from Continuing Operations before Income Taxes, Domestic-->
  <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-69576000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic>
  <!--Income (Loss) from Continuing Operations before Income Taxes, Domestic-->
  <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic contextRef="c20160101to20161231" unitRef="U001" decimals="-3">-57466000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic>
  <!--Income (Loss) from Continuing Operations before Income Taxes, Domestic-->
  <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic contextRef="c20170101to20171231" unitRef="U001" decimals="-3">-5289000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic>
  <!--Income (Loss) from Continuing Operations before Income Taxes, Foreign-->
  <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign contextRef="c20160101to20161231" unitRef="U001" decimals="-3">0</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign>
  <!--Income (Loss) from Continuing Operations before Income Taxes, Foreign-->
  <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-6580000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign>
  <!--Income (Loss) from Continuing Operations before Income Taxes, Foreign-->
  <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign contextRef="c20170101to20171231" unitRef="U001" decimals="-3">-11474000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign>
  <!--Income (Loss) from Continuing Operations before Equity Method Investments, Income Taxes, Noncontrolling Interest-->
  <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments contextRef="c20160101to20161231" unitRef="U001" decimals="-3">-57466000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments>
  <!--Income (Loss) from Continuing Operations before Equity Method Investments, Income Taxes, Noncontrolling Interest-->
  <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-76156000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments>
  <!--Income (Loss) from Continuing Operations before Equity Method Investments, Income Taxes, Noncontrolling Interest-->
  <us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments contextRef="c20170101to20171231" unitRef="U001" decimals="-3">-16763000</us-gaap:IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments>
  <!--Income Tax Expense (Benefit)-->
  <us-gaap:IncomeTaxExpenseBenefit contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-291141000</us-gaap:IncomeTaxExpenseBenefit>
  <!--Income Tax Expense (Benefit)-->
  <us-gaap:IncomeTaxExpenseBenefit contextRef="c20160101to20161231" unitRef="U001" decimals="-3">2934000</us-gaap:IncomeTaxExpenseBenefit>
  <!--Income Tax Expense (Benefit)-->
  <us-gaap:IncomeTaxExpenseBenefit contextRef="c20170101to20171231" unitRef="U001" decimals="-3">-5980000</us-gaap:IncomeTaxExpenseBenefit>
  <!--Income Tax Disclosure [Text Block]-->
  <us-gaap:IncomeTaxDisclosureTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;5. Income Taxes&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Loss before income tax (benefit) expense is comprised of (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;United States&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(69,576&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,289&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(57,466&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Foreign&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(6,580&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(11,474&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Loss before income tax (benefit) expense&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(76,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(16,763&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(57,466&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our income tax (benefit) expense was as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Current:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Federal&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;438&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(7,460&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,067&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;State&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,442&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,246&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,867&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Foreign&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;374&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;234&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total current income tax (benefit) expense&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(630&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,980&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Federal&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(290,511&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;State&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total deferred income tax (benefit) expense&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(290,511&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total income tax (benefit) expense&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(291,141&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,980&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,934&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The reconciliation between our effective tax rate on loss from continuing operations and the statutory U.S. tax rate is as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="22" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Pre-tax loss&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(76,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(16,763&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(57,466&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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font-family: 'Times New Roman', Times, serif;"&gt;382.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)%&lt;/font&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="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Significant components of our deferred tax assets and liabilities as of December 31, 2018 and 2017 are as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred Tax Assets:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net operating loss carryovers&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;89,717&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;153,575&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D credits&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;313,652&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;240,290&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;27,381&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;54,302&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Stock-based compensation&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;61,027&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;40,090&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Intangible and capital assets&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;49,007&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;672&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Other&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,275&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;12,164&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total deferred tax assets&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;549,059&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;501,093&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred Tax Liabilities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(32,391&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net deferred tax asset&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;525,041&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;468,702&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Valuation allowance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(234,245&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(468,702&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total net deferred tax assets and liabilities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;290,796&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We have adjusted all prior year tax amounts to reflect the tax impact of our adoption of Topic 606.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have historically recorded a valuation allowance against all our net deferred tax assets due to cumulative financial statement losses. However, in the fourth quarter of 2018, we reversed the valuation allowance previously recorded against Ionis&amp;#8217; stand-alone U.S. federal net deferred tax assets, resulting in a one-time non-cash tax benefit of $332.1 million. Given our current stand-alone Ionis pre-tax income, and assuming we maintain this current level of Ionis stand-alone pre-tax income, we expect to generate income before taxes in the U.S. in future periods at a level that would result in us fully utilizing our U.S. federal net operating loss carryforwards and most of our Research and Development and Orphan Drug tax credit carryforwards over the next three years.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We continue to maintain a full valuation allowance of $234.2 million against all of Akcea&amp;#8217;s net deferred tax assets and the net state deferred tax assets of Ionis at December 31, 2018 due to uncertainties related to our ability to realize the tax benefits associated with these assets.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our valuation allowance decreased by $234.5 million from December 31, 2017 to December 31, 2018.&amp;#160; The net decrease relates primarily to the reversal of the valuation allowance previously recorded against Ionis&amp;#8217; stand-alone U.S. federal net deferred tax assets, offset by current year utilization of a portion of our net operating loss carry forwards.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At December 31, 2018, we had federal and state, primarily California, tax net operating loss carryforwards of $284.6 million and $808.7 million, respectively. Our federal tax loss carryforwards will begin to expire in 2033, unless we use them before then. Our California loss carryforwards continued to expire in 2018. At December 31, 2018, we also had federal and California research and development tax credit carryforwards of $288.9 million and $68.4 million, respectively. Our Federal research and development tax credit carryforwards began to expire in 2018. Our California research and development tax credit carryforwards are available indefinitely.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the ownership change limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation may result in the expiration of net operating losses and credits before utilization.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;On December 22, 2017, the U.S. government enacted comprehensive tax legislation commonly referred to as the Tax Cuts and Jobs Act of 2017, or the Tax Act. The Tax Act made broad and complex changes to the U.S. tax code, including, but not limited to, reducing the U.S. federal corporate income tax rate to 21 percent, imposing a mandatory one-time transition tax on certain unrepatriated earnings of foreign subsidiaries and eliminating the corporate alternative minimum tax, or AMT, and changing how existing AMT credits can be realized. We were required to recognize the tax effect of the tax law changes the year of enactment. In order to calculate these effects, we were required to determine the transition tax amount, remeasure our U.S. deferred tax assets and liabilities, and consider the impact to our AMT tax credit carryforwards. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For the year ended December 31, 2017, we recorded provisional amounts in accordance with that guidance where it was possible for us to make reasonable estimates of the effects of the Tax Act. We evaluated the decrease in our corporate tax rate and recorded a provisional, one-time tax expense of $107.3 million at December 31, 2017. We fully offset our tax effect by a decrease in our valuation allowance which resulted in no net tax effect in 2017.&lt;/font&gt; During the fourth quarter of 2018, we completed our accounting for all aspects of the Tax Act. We did not identify material changes from our 2017 provisional analysis.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We analyze filing positions in all U.S. federal, state and foreign jurisdictions where we file income tax returns, and all open tax years in these jurisdictions to determine if we have any uncertain tax positions on any of our income tax returns. We recognize the impact of an uncertain tax position on an income tax return at the largest amount that the relevant taxing authority is more-likely-than not to sustain upon audit. We do not recognize uncertain income tax positions if they have less than 50 percent likelihood of the applicable tax authority sustaining our position.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes our gross unrecognized tax benefits (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Beginning balance of unrecognized tax benefits&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;78,014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66,999&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;51,257&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Settlement of prior period tax positions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4,033&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Decrease for prior period tax positions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,814&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Increase for prior period tax positions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,520&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7,928&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Increase for current period tax positions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3,101&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;9,495&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11,847&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ending balance of unrecognized tax benefits&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;68,301&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;78,014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66,999&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Included in the balance of unrecognized tax benefits at December&amp;#160;31, 2018, is $55.5 million that could impact our effective tax rate, subject to our remaining valuation allowance.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We do not foresee any material changes to our gross unrecognized tax benefits within the next twelve months.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize interest and/or penalties related to income tax matters in income tax expense. We did not recognize any accrued interest and penalties related to gross unrecognized tax benefits during the year ended December 31, 2018.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are subject to taxation in the U.S. and various state and foreign jurisdictions. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our tax years for 1999 through 2018 are subject to examination by the U.S. federal, state and foreign tax authorities.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries as we consider those earnings to be permanently reinvested. It is not practicable for us to calculate the amount of unrecognized deferred tax liabilities associated with these earnings.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are subject to periodic audits by domestic and foreign tax authorities; however, we are not aware of any audits at this time. We believe that we have appropriate support for the income tax positions taken on our tax returns and our accruals for tax liabilities are adequate for all open audit years. Our conclusions are based on an assessment of many factors, including past experience and interpretations of tax law applied to the facts of each matter.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:IncomeTaxDisclosureTextBlock>
  <!--Effective Income Tax Rate Reconciliation, Change in Deferred Tax Assets Valuation Allowance, Amount-->
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  <!--Effective Income Tax Rate Reconciliation, Change in Deferred Tax Assets Valuation Allowance, Amount-->
  <us-gaap:IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance contextRef="c20170101to20171231" unitRef="U001" decimals="-3">-86296000</us-gaap:IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance>
  <!--Effective Income Tax Rate Reconciliation, Change in Deferred Tax Assets Valuation Allowance, Amount-->
  <us-gaap:IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance contextRef="c20160101to20161231" unitRef="U001" decimals="-3">46402000</us-gaap:IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance>
  <!--Effective Income Tax Rate Reconciliation, Change in Deferred Tax Assets Valuation Allowance, Amount-->
  <us-gaap:IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-277924000</us-gaap:IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance>
  <!--Effective Income Tax Rate Reconciliation, Nondeductible Expense, Share-based Compensation Cost, Amount-->
  <us-gaap:IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-4199000</us-gaap:IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost>
  <!--Effective Income Tax Rate Reconciliation, Nondeductible Expense, Share-based Compensation Cost, Amount-->
  <us-gaap:IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost contextRef="c20160101to20161231" unitRef="U001" decimals="-3">0</us-gaap:IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost>
  <!--Effective Income Tax Rate Reconciliation, Nondeductible Expense, Share-based Compensation Cost, Amount-->
  <us-gaap:IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost contextRef="c20170101to20171231" unitRef="U001" decimals="-3">-14337000</us-gaap:IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost>
  <!--Effective Income Tax Rate Reconciliation, Other Adjustments, Amount-->
  <us-gaap:IncomeTaxReconciliationOtherAdjustments contextRef="c20180101to20181231" unitRef="U001" decimals="-3">1633000</us-gaap:IncomeTaxReconciliationOtherAdjustments>
  <!--Effective Income Tax Rate Reconciliation, Other Adjustments, Amount-->
  <us-gaap:IncomeTaxReconciliationOtherAdjustments contextRef="c20160101to20161231" unitRef="U001" decimals="-3">-236000</us-gaap:IncomeTaxReconciliationOtherAdjustments>
  <!--Effective Income Tax Rate Reconciliation, Other Adjustments, Amount-->
  <us-gaap:IncomeTaxReconciliationOtherAdjustments contextRef="c20170101to20171231" unitRef="U001" decimals="-3">-89000</us-gaap:IncomeTaxReconciliationOtherAdjustments>
  <!--Effective Income Tax Rate Reconciliation, Foreign Income Tax Rate Differential, Amount-->
  <us-gaap:IncomeTaxReconciliationForeignIncomeTaxRateDifferential contextRef="c20170101to20171231" unitRef="U001" decimals="-3">4299000</us-gaap:IncomeTaxReconciliationForeignIncomeTaxRateDifferential>
  <!--Effective Income Tax Rate Reconciliation, Foreign Income Tax Rate Differential, Amount-->
  <us-gaap:IncomeTaxReconciliationForeignIncomeTaxRateDifferential contextRef="c20160101to20161231" unitRef="U001" decimals="-3">0</us-gaap:IncomeTaxReconciliationForeignIncomeTaxRateDifferential>
  <!--Effective Income Tax Rate Reconciliation, Foreign Income Tax Rate Differential, Amount-->
  <us-gaap:IncomeTaxReconciliationForeignIncomeTaxRateDifferential contextRef="c20180101to20181231" unitRef="U001" decimals="-3">1735000</us-gaap:IncomeTaxReconciliationForeignIncomeTaxRateDifferential>
  <!--Effective Income Tax Rate Reconciliation at Federal Statutory Income Tax Rate, Amount-->
  <us-gaap:IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate contextRef="c20170101to20171231" unitRef="U001" decimals="-3">-5867000</us-gaap:IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate>
  <!--Effective Income Tax Rate Reconciliation at Federal Statutory Income Tax Rate, Amount-->
  <us-gaap:IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-15993000</us-gaap:IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate>
  <!--Effective Income Tax Rate Reconciliation at Federal Statutory Income Tax Rate, Amount-->
  <us-gaap:IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate contextRef="c20160101to20161231" unitRef="U001" decimals="-3">-20113000</us-gaap:IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate>
  <!--Effective Income Tax Rate Reconciliation, Nondeductible Expense, Other, Amount-->
  <us-gaap:IncomeTaxReconciliationNondeductibleExpenseOther contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-569000</us-gaap:IncomeTaxReconciliationNondeductibleExpenseOther>
  <!--Effective Income Tax Rate Reconciliation, Nondeductible Expense, Other, Amount-->
  <us-gaap:IncomeTaxReconciliationNondeductibleExpenseOther contextRef="c20160101to20161231" unitRef="U001" decimals="-3">324000</us-gaap:IncomeTaxReconciliationNondeductibleExpenseOther>
  <!--Effective Income Tax Rate Reconciliation, Nondeductible Expense, Other, Amount-->
  <us-gaap:IncomeTaxReconciliationNondeductibleExpenseOther contextRef="c20170101to20171231" unitRef="U001" decimals="-3">2548000</us-gaap:IncomeTaxReconciliationNondeductibleExpenseOther>
  <!--Effective Income Tax Rate Reconciliation, Change in Enacted Tax Rate, Amount-->
  <us-gaap:IncomeTaxReconciliationChangeInEnactedTaxRate contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-1808000</us-gaap:IncomeTaxReconciliationChangeInEnactedTaxRate>
  <!--Effective Income Tax Rate Reconciliation, Change in Enacted Tax Rate, Amount-->
  <us-gaap:IncomeTaxReconciliationChangeInEnactedTaxRate contextRef="c20160101to20161231" unitRef="U001" decimals="-3">0</us-gaap:IncomeTaxReconciliationChangeInEnactedTaxRate>
  <!--Effective Income Tax Rate Reconciliation, Change in Enacted Tax Rate, Amount-->
  <us-gaap:IncomeTaxReconciliationChangeInEnactedTaxRate contextRef="c20170101to20171231" unitRef="U001" decimals="-3">114832000</us-gaap:IncomeTaxReconciliationChangeInEnactedTaxRate>
  <!--Income Tax, Policy [Policy Text Block]-->
  <us-gaap:IncomeTaxPolicyTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Income Taxes&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development credit carryforwards. We record a valuation allowance when necessary to reduce deferred tax assets to the amount we expect to realize.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes. Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for income taxes in the period in which such determination is made.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted.&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be realized.&amp;#160;&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For U.S. federal income tax purposes, we are required to file separate U.S. federal income tax returns for Ionis and Akcea. We began deconsolidating Akcea for U.S. federal income tax purposes upon Akcea&amp;#8217;s initial public offering. As a result, we are required to assess our Ionis stand-alone and Akcea&amp;#8217;s valuation allowances separately even though we consolidate Akcea&amp;#8217;s financial results in our consolidated financial statements. We continue to file combined state tax returns in most jurisdictions. As a result, we continue to assess the state portion of our valuation allowance for those jurisdictions on a consolidated basis.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have historically recorded a valuation allowance against all our net deferred tax assets due to cumulative financial statement losses. However, in the fourth quarter of 2018, we reversed the valuation allowance previously recorded against our Ionis stand-alone U.S. federal net deferred tax assets, resulting in a one-time non-cash tax benefit of $332.1 million. Given our current stand-alone Ionis pre-tax income, and assuming we maintain this current level of Ionis stand-alone pre-tax income, we expect to generate income before taxes in the U.S. in future periods at a level that would result in us fully utilizing our U.S. federal net operating loss carryforwards and most of our Research and Development and Orphan Drug tax credit carryforwards over the next three years.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We continue to maintain a full valuation allowance of $234.2 million against all of Akcea&amp;#8217;s net deferred tax assets and the net state deferred tax assets of Ionis at December 31, 2018 due to uncertainties related to our ability to realize the tax benefits associated with these assets.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:IncomeTaxPolicyTextBlock>
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  <!--Effective Income Tax Rate Reconciliation, State and Local Income Taxes, Amount-->
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  <!--Effective Income Tax Rate Reconciliation, Tax Credit, Amount-->
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  <!--Effective Income Tax Rate Reconciliation, Tax Credit, Amount-->
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  <!--Effective Income Tax Rate Reconciliation, Tax Credit, Amount-->
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  <!--Effective Income Tax Rate Reconciliation, Prior Year Income Taxes, Amount-->
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  <!--Effective Income Tax Rate Reconciliation, Prior Year Income Taxes, Amount-->
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  <!--Income taxes-->
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  <!--Income taxes-->
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  <!--Income taxes-->
  <us-gaap:IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable contextRef="c20160101to20161231" unitRef="U001" decimals="-3">1069000</us-gaap:IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable>
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  <!--Increase (Decrease) in Contract with Customer, Liability-->
  <us-gaap:IncreaseDecreaseInContractWithCustomerLiability contextRef="c20180101to20181231" unitRef="U001" decimals="-3">494254000</us-gaap:IncreaseDecreaseInContractWithCustomerLiability>
  <!--Increase (Decrease) in Contract with Customer, Liability-->
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  <!--Increase (Decrease) in Contract with Customer, Asset-->
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  <!--Increase (Decrease) in Contract with Customer, Asset-->
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  <!--Increase (Decrease) in Contract with Customer, Asset-->
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  <!--Increase (Decrease) in Accounts Payable-->
  <us-gaap:IncreaseDecreaseInAccountsPayable contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-655000</us-gaap:IncreaseDecreaseInAccountsPayable>
  <!--Increase (Decrease) in Accounts Payable-->
  <us-gaap:IncreaseDecreaseInAccountsPayable contextRef="c20160101to20161231" unitRef="U001" decimals="-3">-10677000</us-gaap:IncreaseDecreaseInAccountsPayable>
  <!--Increase (Decrease) in Accounts Payable-->
  <us-gaap:IncreaseDecreaseInAccountsPayable contextRef="c20170101to20171231" unitRef="U001" decimals="-3">1784000</us-gaap:IncreaseDecreaseInAccountsPayable>
  <!--Increase (Decrease) in Income Taxes Receivable-->
  <us-gaap:IncreaseDecreaseInIncomeTaxesReceivable contextRef="c20180101to20181231" unitRef="U001" decimals="-3">223000</us-gaap:IncreaseDecreaseInIncomeTaxesReceivable>
  <!--Increase (Decrease) in Income Taxes Receivable-->
  <us-gaap:IncreaseDecreaseInIncomeTaxesReceivable contextRef="c20170101to20171231" unitRef="U001" decimals="-3">9114000</us-gaap:IncreaseDecreaseInIncomeTaxesReceivable>
  <!--Increase (Decrease) in Income Taxes Receivable-->
  <us-gaap:IncreaseDecreaseInIncomeTaxesReceivable contextRef="c20160101to20161231" unitRef="U001" decimals="-3">0</us-gaap:IncreaseDecreaseInIncomeTaxesReceivable>
  <!--Increase (Decrease) in Inventories-->
  <us-gaap:IncreaseDecreaseInInventories contextRef="c20160101to20161231" unitRef="U001" decimals="-3">590000</us-gaap:IncreaseDecreaseInInventories>
  <!--Increase (Decrease) in Inventories-->
  <us-gaap:IncreaseDecreaseInInventories contextRef="c20180101to20181231" unitRef="U001" decimals="-3">-1400000</us-gaap:IncreaseDecreaseInInventories>
  <!--Increase (Decrease) in Inventories-->
  <us-gaap:IncreaseDecreaseInInventories contextRef="c20170101to20171231" unitRef="U001" decimals="-3">2493000</us-gaap:IncreaseDecreaseInInventories>
  <!--Increase (Decrease) in Other Operating Assets-->
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  <!--Increase (Decrease) in Other Operating Assets-->
  <us-gaap:IncreaseDecreaseInOtherOperatingAssets contextRef="c20170101to20171231" unitRef="U001" decimals="-3">58367000</us-gaap:IncreaseDecreaseInOtherOperatingAssets>
  <!--Increase (Decrease) in Other Operating Assets-->
  <us-gaap:IncreaseDecreaseInOtherOperatingAssets contextRef="c20160101to20161231" unitRef="U001" decimals="-3">-1603000</us-gaap:IncreaseDecreaseInOtherOperatingAssets>
  <!--Increase (Decrease) in Other Employee-Related Liabilities-->
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  <!--Increase (Decrease) in Other Employee-Related Liabilities-->
  <us-gaap:IncreaseDecreaseInOtherEmployeeRelatedLiabilities contextRef="c20160101to20161231" unitRef="U001" decimals="-3">8121000</us-gaap:IncreaseDecreaseInOtherEmployeeRelatedLiabilities>
  <!--Increase (Decrease) in Other Employee-Related Liabilities-->
  <us-gaap:IncreaseDecreaseInOtherEmployeeRelatedLiabilities contextRef="c20180101to20181231" unitRef="U001" decimals="-3">4117000</us-gaap:IncreaseDecreaseInOtherEmployeeRelatedLiabilities>
  <!--Shares issuable related to stock-based compensation (in shares)-Restricted Stock [Member]-->
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  <!--Shares issuable related to stock-based compensation (in shares)-Employee Stock Option [Member]-->
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  <!--Shares issuable related to stock-based compensation (in shares)-Employee Stock Option [Member]-->
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  <!--Shares issuable related to stock-based compensation (in shares)-Restricted Stock [Member]-->
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  <!--Shares issuable related to stock-based compensation (in shares)-Restricted Stock [Member]-->
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  <!--Shares issuable related to stock-based compensation (in shares)-Restricted Stock [Member]-->
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  <!--Shares issuable related to stock-based compensation (in shares)-Employee Stock Option [Member]-->
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  <!--Incremental Common Shares Attributable to Dilutive Effect of Conversion of Debt Securities-->
  <us-gaap:IncrementalCommonSharesAttributableToConversionOfDebtSecurities contextRef="c20181001to20181231" unitRef="U002" decimals="-3">10260000</us-gaap:IncrementalCommonSharesAttributableToConversionOfDebtSecurities>
  <!--Intangible Assets, Finite-Lived, Policy [Policy Text Block]-->
  <us-gaap:IntangibleAssetsFiniteLivedPolicy contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was 10.1 years at December 31, 2018.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The cost of our patents capitalized on our consolidated balance sheet at December 31, 2018 and 2017 was $32.7 million and $30.8 million, respectively. Accumulated amortization related to patents was $8.7 million and $8.8 million at December 31, 2018 and 2017, respectively.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ending December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amortization&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(in millions)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2019&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2020&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2021&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2022&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2023&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications that have future value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2018, 2017 and 2016, patent expenses were $2.6 million, $2.1 million and $3.9 million, respectively, and included non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $0.8 million, $0.4 million and $2.3 million, respectively.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:IntangibleAssetsFiniteLivedPolicy>
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  <us-gaap:InventoryPolicyTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Inventory Valuation&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We reflect our inventory on our consolidated balance sheet at the lower of cost or market value under the first-in, first-out method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials they have alternative future uses. We include in inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and, as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We expense these costs as R&amp;amp;D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency.&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We obtained the first regulatory approval for TEGSEDI in July 2018. At December 31, 2018, our physical inventory for TEGSEDI included API that we produced prior to when we obtained regulatory approval and accordingly has no cost basis as we had previously expensed the costs as R&amp;amp;D expenses.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development and historical write-offs. We did not record any inventory write-offs for the years ended December 31, 2018, 2017 or 2016. Total inventory was $8.6 million and $10.0 million as of December 31, 2018 and 2017, respectively.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:InventoryPolicyTextBlock>
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  <us-gaap:InvestmentsClassifiedByContractualMaturityDateTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2018:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;One year or less&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;77&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;After one year but within two years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;20&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;After two years but within three and one half years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;100&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:InvestmentsClassifiedByContractualMaturityDateTableTextBlock>
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  <us-gaap:LegalMattersAndContingenciesTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;9. Legal Proceedings&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we evaluate the status of each legal matter and assess our potential financial exposure. If the potential loss from any legal proceeding is considered probable and the amount can be reasonably estimated, we accrue a liability for the estimated loss. Significant judgment is required to determine the probability of a loss and whether the amount of the loss is reasonably estimable. The outcome of any proceeding is not determinable in advance. As a result, the assessment of a potential liability and the amount of accruals recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the potential liability related to the legal proceeding, and may revise our estimates.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Gilead Litigation&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In August 2013, Gilead Sciences Inc. filed a suit in the U.S. District Court of Northern District of California related to U.S. Patent Nos. 7,105,499 and 8,481,712, which are jointly owned by Merck Sharp &amp;amp; Dohme Corp. and Ionis Pharmaceuticals, Inc.&amp;#160;In the suit Gilead asked the court to determine that Gilead&amp;#8217;s activities do not infringe any valid claim of the named patents and that the patents are not valid. We and Merck Sharp &amp;amp; Dohme Corp. filed our answer denying Gilead&amp;#8217;s noninfringement and invalidity contentions, contending that Gilead&amp;#8217;s commercial sale and offer for sale of sofosbuvir prior to the expiration of the &amp;#8216;499 and &amp;#8216;712 patents infringes those patents, and requesting monetary damages to compensate for such infringement. In the trial for this case held in March 2016, the jury upheld all &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;ten&lt;/font&gt; of the asserted claims of the patents-in-suit. The jury then decided that we and Merck are entitled to &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;four percent of $5 &lt;/font&gt;billion in past sales of sofosbuvir. Gilead has stated it would appeal the jury&amp;#8217;s finding of validity. In the meantime, Gilead asserted &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;two &lt;/font&gt;additional non-jury defenses: waiver and unclean hands. Although the judge rejected the waiver defense, she granted Gilead&amp;#8217;s motion claiming that the patents are unenforceable against it under the doctrine of unclean hands. We believe this ruling is contrary to the relevant law and the facts of the case. Accordingly, in July 2016, together with Merck we appealed the decision to the Court of Appeals for the Federal Circuit. Gilead cross-appealed on the issue of validity. In April 2018, the Court of Appeals issued its ruling affirming the District Court&amp;#8217;s finding of unenforceability based on unclean hands.&amp;#160;Having upheld the ruling that the patents are unenforceable against Gilead, the court did not reach the question of validity. In September 2018, we filed a petition requesting a hearing before the Supreme Court, asserting that it was improper for the trial court to overturn the jury verdict on the basis of the equitable defense of unclean hands. In January 2019, the Supreme Court denied our petition. Under our agreement with Merck, Merck is responsible for the costs of this suit.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:LegalMattersAndContingenciesTextBlock>
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  <!--Liabilities, Current-->
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  <us-gaap:NewAccountingPronouncementsPolicyPolicyTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Impact of Recently Issued Accounting Standards&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In February 2016, the FASB issued amended accounting guidance related to lease accounting, which will require us to record all leases with a term longer than one year on our balance sheet. When we record leases on our balance sheet under the new guidance, we will record a liability with a value equal to the present value of payments we will make over the life of the lease (lease liability) and an asset representing the underlying leased asset (right of use asset). The new accounting guidance requires us to determine if our leases are operating or financing leases. We will record expense for operating leases on a straight-line basis as an operating expense. If we determine a lease is a financing&amp;#160;lease, we will record both interest and amortization expense and generally the expense will be higher in the earlier periods of the lease. We adopted this guidance on January 1, 2019 and adjusted our opening balance sheet on that date. We elected the available practical expedients. The most significant impact was the recognition of right of use assets and lease liabilities for our operating leases. We are in the process of finalizing the impact of the adoption. The adoption will not have an impact on our consolidated statement of operations or statement of cash flows.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In June 2016, the FASB issued guidance that changes the measurement of credit losses for most financial assets and certain other instruments. If we have credit losses, this updated guidance requires us to record allowances for these instruments under a new expected credit loss model. This model requires us to estimate the expected credit loss of an instrument over its lifetime, which represents the portion of the amortized cost basis we do not expect to collect. The new guidance requires us to remeasure our allowance in each reporting period we have credit losses. The new standard is effective for annual and interim periods beginning after December 15, 2019. Early adoption is permitted for periods beginning after December 15, 2018. When we adopt the new standard, we will make any adjustments to beginning balances through a cumulative-effect adjustment to accumulated deficit on that date. We plan to adopt this guidance on January 1, 2020. We are currently assessing the effects it will have on our consolidated financial statements and disclosures.&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In February 2018, the FASB issued updated guidance for reclassification of tax effects from accumulated other comprehensive income (loss). The updated guidance gives entities an option to reclassify amounts included in accumulated other comprehensive income (loss) that under the Tax Act do not have a way to be relieved, and allows a one-time reclassification to retained earnings. The updated guidance is effective for all entities for fiscal years beginning after December 31, 2018, and interim periods within those fiscal years. We have decided not to record the reclassification adjustments provided by this guidance.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In June 2018, the FASB issued updated guidance to simplify the accounting for stock-based compensation expense for nonemployees. Specifically, we are now expensing grants to nonemployees in a similar manner as grants to employees. Previously, we had to re-value these grants at each reporting period to reflect the current fair value. Under the amended guidance, we value grants to nonemployees when we grant them and we will not adjust their value for future changes. We adopted this guidance in the second quarter of 2018. The updated guidance did not have a material impact to our financial results.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In November 2018, the FASB issued clarifying guidance of the interaction between the collaboration accounting guidance and the new revenue recognition guidance we adopted on January 1, 2018 (Topic 606). The clarifying guidance included the following:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;When a participant is considered a customer in a collaborative arrangement, all of the associated accounting under Topic 606 should be applied;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Adds &amp;#8220;unit of account&amp;#8221; concept to collaboration accounting guidance to align with Topic 606. This is used to determine if revenue is recognized or if a contra expense is recognized from consideration received under a collaboration; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Precludes revenue from being recognized under Topic 606 when a transaction with a collaborative partner is determined not be a customer and is not directly related to the sales to third parties.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The updated guidance is effective for public entities for fiscal years beginning after December 15, 2019, and interim periods within those fiscal years. 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  <!--Organization, Consolidation, Basis of Presentation, Business Description and Accounting Policies [Text Block]-->
  <us-gaap:OrganizationConsolidationBasisOfPresentationBusinessDescriptionAndAccountingPoliciesTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;1. Organization and Significant Accounting Policies&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basis of Presentation&lt;/div&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals,&amp;#160;Inc. (&amp;#8220;we&amp;#8221;, &amp;#8220;us&amp;#8221; or &amp;#8220;our&amp;#8221;) and the consolidated results of our majority-owned affiliate,&amp;#160;Akcea Therapeutics, Inc., which we formed in December 2014. In July 2017, Akcea completed an initial public offering, or IPO, and therefore beginning in July 2017, we no longer own 100 percent of Akcea. &lt;/font&gt;From the closing of Akcea&amp;#8217;s IPO in July 2017 through mid-April 2018, we owned approximately 68 percent&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;of Akcea. In the second, third and fourth quarters of 2018, we received additional shares of Akcea&amp;#8217;s stock related to our license of TEGSEDI and AKCEA-TTR-L&lt;sub&gt;Rx&lt;/sub&gt; to Akcea, increasing our ownership percentage to approximately 75 percent. We reflected the increase in our ownership in these financial statements. In the first quarter of 2019, Akcea will pay us a $75 million sublicense fee in Akcea common stock, as a result of Novartis&amp;#8217; license of AKCEA-APO(a)-L&lt;sub&gt;Rx&lt;/sub&gt; in February 2019. We will receive 2.8 million shares of Akcea common stock for the sublicense fee. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Refer to the noncontrolling interest in Akcea section in this note for further information related to our accounting for our investment in Akcea.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Organization and Business Activity&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation in April&amp;#160;1991. We were organized principally to develop human therapeutic medicines using antisense technology. In December 2015, we changed our name from Isis Pharmaceuticals, Inc. to Ionis Pharmaceuticals, Inc.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Basic and Diluted Net Income (Loss) per Share&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Basic net income (loss) per share&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The calculation of total net income (loss) attributable to our common stockholders for 2018 and 2017 considered our net income for Ionis on a stand-alone basis plus our share of Akcea&amp;#8217;s net loss for the period. During 2016, we owned 100 percent of Akcea. To calculate the portion of Akcea&amp;#8217;s net loss attributable to our ownership for 2018 and 2017, we multiplied Akcea&amp;#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our&amp;#160;total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for 2018 and 2017.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our basic net income per share for &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2018&lt;/font&gt;, was calculated as follows (in thousands, except per share amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Income (Loss)&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Portion of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;59,812&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2.74&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(163,938&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(163,938&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;440,806&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;276,868&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;132,320&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.09&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Prior to Akcea&amp;#8217;s IPO in July 2017, we owned Akcea series A convertible preferred stock, which included a six percent cumulative dividend. Upon completion of Akcea&amp;#8217;s IPO in July 2017, our preferred stock was converted into common stock on a 1:1 basis. The preferred stock dividend was not paid at the IPO because the IPO was not a liquidation event or a change in control. During 2017, Akcea used a two-class method to compute its net income (loss) per share because it had both common and preferred shares outstanding during the periods. The two-class method required Akcea to calculate its net income (loss) per share&amp;#160;for each class of stock by dividing total distributable losses applicable to preferred and common stock, including the&amp;#160;six percent&amp;#160;cumulative dividend contractually due to series A convertible preferred shareholders, by the weighted-average of preferred and common shares outstanding during the requisite period. Since Akcea used the two-class method, accounting rules required us to include our portion of Akcea&amp;#8217;s net income (loss) per share for both Akcea&amp;#8217;s common and preferred shares that we owned in our calculation of basic and diluted net income (loss) per share for year ended December 31, 2017.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our basic net income per share for 2017 as follows (in thousands, except per share amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Loss&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Portion of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;20,669&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3.08&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(63,638&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Preferred shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;15,748&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1.80&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(28,346&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(91,984&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;110,776&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,792&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Dilutive net income (loss per share)&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For 2018 and 2017, we had net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our diluted net income per share for 2018 as follows &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(in thousands except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Income&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Numerator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Denominator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per-Share&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;276,868&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;132,320&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.09&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effect of dilutive securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon exercise of stock options&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,216&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon restricted stock award issuance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;514&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our ESPP&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income available to Ionis common stockholders, plus assumed conversions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;276,868&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;134,056&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We calculated our diluted net income per share for 2017 as follows &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(in thousands except per share amounts):&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Income&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Numerator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Denominator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per-Share&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,792&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effect of dilutive securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon exercise of stock options&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,619&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon restricted stock award issuance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;459&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our ESPP&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income available to Ionis common stockholders, plus assumed conversions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,792&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;126,098&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For 2018 and 2017, the calculation excluded our convertible notes because the effect on diluted earnings per share was anti-dilutive.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For 2016, 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;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1 percent convertible senior notes;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2&amp;#190; percent convertible senior notes;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dilutive stock options;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Unvested restricted stock units; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Employee Stock Purchase Plan, or ESPP.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Revenue Recognition&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Adoption of New Revenue Recognition Accounting Standard (Topic 606)&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In May 2014, the FASB issued accounting guidance on the recognition of revenue from customers. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;This guidance supersedes the revenue recognition requirements we previously followed in Accounting Standards Codification, or ASC, Topic 605, &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Revenue Recognition&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, or Topic 605, and created a new Topic 606, &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Revenue from Contracts with Customers&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, or Topic 606. &lt;/font&gt;Under Topic 606, an entity will recognize revenue when it transfers control of promised goods or services to customers in an amount that reflects what the entity expects to receive in exchange for the goods or services. Further, an entity will recognize revenue upon satisfying the performance obligation(s) under the related contract. We adopted Topic 606 on January 1, 2018 under the full retrospective approach, which required us to revise our prior period revenue. Under Topic 606, we were required to review all of our ongoing collaboration agreements in which we recognized revenue after January 1, 2016. We were required to assess what our revenue would have been for the period from January 1, 2016 to December 31, 2017 under Topic 606. As a result of this analysis, we determined that the cumulative revenue we would have recognized under Topic 606 decreased by $86.1 million. We recorded this amount as a cumulative adjustment to our accumulated deficit as of January 1, 2016 on our revised statement of stockholders&amp;#8217; equity. We have labeled our prior period financial statements &amp;#8220;as revised&amp;#8221; to indicate the change required under the accounting rules.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following tables summarize the adjustments we were required to make to amounts we originally reported in 2017 and 2016 to adopt Topic 606 (in thousands, except per share amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Consolidated Balance Sheet&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;At December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Current portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;106,465&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,871&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;125,336&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Long-term portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;112,540&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;-&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;112,540&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;9,519&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7,474&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;122,059&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120,014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Research and development revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;385,607&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,558&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;394,165&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;507,666&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;514,179&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;24,534&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;31,047&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(17,296&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(10,783&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,970&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,316&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;346&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income per share, basic and diluted&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.08&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Revenue:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Commercial revenue:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;SPINRAZA royalties&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;883&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;883&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;19,839&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21,884&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;20,722&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;22,767&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Research and development revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;325,898&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;24,111&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(60,400&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(60,400&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss) per share, basic and diluted&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.72&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.22&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.50&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Consolidated Statements of Cash Flows&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; 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width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27.15pt; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;36,695&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;30,182&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at beginning of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at end of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;129,630&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;129,630&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(86,556&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(60,400&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27.15pt; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(59,150&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(85,306&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at beginning of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;128,797&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;128,797&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at end of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under Topic 606, compared to Topic 605, our total revenue increased $6.5 million for &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2017&lt;/font&gt; and $26.2 million for &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2016&lt;/font&gt;. The change in our revenue was primarily due to:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;A change in how we recognize milestone payments:&lt;/u&gt;&lt;/font&gt; Topic 606 requires us to amortize more of the milestone payments we achieve, rather than recognizing the milestone payments in full in the period in which we achieved the milestone event as we did under Topic 605. This change resulted in an increase in R&amp;amp;D revenue recognized for 2017 and 2016 of $23.7 million and $24.1 million, respectively.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;A change in how we calculate revenue for payments we are recognizing into revenue over time:&lt;/u&gt;&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; Under Topic 605, we amortized payments into revenue evenly over the period of our obligations. When we made a change to our estimated completion period, we recognized that change on a prospective basis. Under Topic 606, we are required to use an input method to determine the amount we amortize each reporting period. Each period we review our &amp;#8220;inputs&amp;#8221; such as our level of effort expended, including the time we estimate it will take us to complete the activities or costs incurred, relative to the total expected inputs to satisfy the performance obligation. For certain collaborations, such as Bayer and Novartis, the input method resulted in a change to the revenue we had previously recognized using a straight-line amortization method.&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;This change resulted in a decrease in our R&amp;amp;D revenue of $15.1 million for 2017. This change did not result in an impact to our 2016 R&amp;amp;D revenue.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our updated revenue recognition policy reflecting Topic 606 is as follows:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Our Revenue Sources&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue, we include the amounts in deferred revenue on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as commercial revenue future sales milestone payments and royalties we earn under our partnerships.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Commercial Revenue: TEGSEDI Product Sales, net&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We began adding product sales from TEGSEDI to our commercial revenue in the fourth quarter of 2018. &lt;/font&gt;In the U.S., TEGSEDI is distributed through an exclusive distribution agreement with a third-party logistics company, or 3PL, that takes title to TEGSEDI. The 3PL is our sole customer in the U.S. The 3PL then distributes TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distribute TEGSEDI to health care providers and patients. In Germany, TEGSEDI is distributed through a non-exclusive distribution model with a 3PL that takes title to TEGSEDI. The 3PL is our sole customer in Germany. The 3PL in Germany then distributes TEGSEDI to hospitals and pharmacies.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Research and development revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;amp;D, services, and manufacturing services.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our collaboration agreements are detailed in Note 6, &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements.&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;&amp;#160;&lt;/font&gt;Under each collaboration note we discuss our specific revenue recognition conclusions, including our significant performance obligations under each collaboration.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Steps to Recognize Revenue&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We use a five step process to determine the amount of revenue we should recognize and when we should recognize it. The five step process is as follows:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;1.&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Identify the contract&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the following criteria:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We and our partner approved the contract and we are both committed to perform our obligations;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have identified our rights, our partner&amp;#8217;s rights and the payment terms;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the contract; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We believe collectability is probable.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="margin-bottom: 10pt;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;2.&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Identify the performance obligations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We next identify the distinct goods and services we are required to provide under the contract. Accounting rules refer to these as our performance obligations. We typically have only one performance obligation at the inception of a contract, which is to perform R&amp;amp;D services.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Often times we enter into a collaboration agreement in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights. These items are contingent upon future events that may not occur. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;3.&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Determine the transaction price&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because the payments are not probable. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and are usually based on scientific progress. For example, in the first quarter of 2019, we earned a $35 million milestone payment from Roche when it dosed the first patient in the Phase 3 study of IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt;.&amp;#160; At December 31, 2018, we determined it was not probable that we could earn this milestone payment.&amp;#160;As such, we did not recognize any revenue associated with it in 2018.&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;&amp;#160; &amp;#160;&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;4.&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Allocate the transaction price&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling price.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement. We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected income to present value. The significant inputs we use to determine the projected income of a license could include:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Estimated future product sales;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Estimated royalties on future product sales;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Contractual milestone payments;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expenses we expect to incur;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income taxes; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;A discount rate.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We typically estimate the selling price of R&amp;amp;D services by using our internal estimates of the cost to perform the specific services. The significant inputs we use to determine the selling price of our R&amp;amp;D services include:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The number of internal hours we estimate we will spend performing these services;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The estimated cost of work we will perform;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The estimated cost of work that we will contract with third parties to perform; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The estimated cost of API we will use.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For purposes of determining the stand-alone selling price of the R&amp;amp;D services we perform and the API we will deliver, accounting guidance requires us to include a markup for a reasonable profit margin.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;5.&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Recognize revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;amp;D services. We recognize revenue at a point in time when our partner receives full use of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For R&amp;amp;D services that we recognize over time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;change over the course of the collaboration, they may affect the timing and amount of revenue that we recognize in the current and future periods.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following are examples of when we typically recognize revenue based on the types of payments we receive.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize royalty revenue in the period in which the counterparty sells the related product, which in certain cases may require us to estimate our royalty revenue. &lt;/font&gt;We recognize royalties from SPINRAZA sales in the period Biogen records the sale of SPINRAZA. Our accounting for SPINRAZA royalties did not change as a result of adopting Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Commercial Revenue: TEGSEDI Product Sales, net&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize TEGSEDI product sales in the period &lt;/font&gt;when our customer obtains control of TEGSEDI, which occurs at a point in time upon transfer of title to the customer. We classify payments to customers or other parties in the distribution channel for services that are distinct and priced at fair value as selling, general and administrative expenses in our consolidated statements of operations. Otherwise payments to customers or other parties in the distribution channel that do not meet those criteria are classified as a reduction of revenue, as discussed further below. We exclude from revenues, taxes collected from customers relating to product sales and remitted to governmental authorities.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Reserves for TEGSEDI Product Sales&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We record TEGSEDI product sales at our net sales price, or transaction price. We include in our transaction price estimated reserves for discounts, returns, chargebacks, rebates, co-pay assistance and other allowances that we offer within contracts between us and our customers, wholesalers, health care providers and other indirect customers. We estimate our reserves using the amounts we have earned or what we can claim on the associated sales. We classify our reserves as reductions of accounts receivable when the amount is payable to our customer or a current liability when the amount is payable to a party other than our customer in our consolidated balance sheet. In certain cases, our estimates include a range of possible outcomes that are probability-weighted for relevant factors such as our historical experience, current contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflect our best estimates under the terms of our respective contracts. When calculating our reserves and related product sales, we only recognize amounts to the extent that we consider it probable that we would not have to reverse in a future period a significant amount of the cumulative sales we previously recognized. The actual amounts we receive may ultimately differ from our reserve estimates. If actual amounts in the future vary from our estimates, we will adjust these estimates, which would affect our net TEGSEDI product sales in the respective period.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following are the components of variable consideration related to TEGSEDI product sales:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Chargebacks: &lt;/font&gt;In the U.S., we estimate obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charges us for the difference between what it pays for the product and the selling price to the qualified healthcare providers. We record reserves for these chargebacks related to TEGSEDI product sales to our U.S. customer during the reporting period. We also estimate the amount of product remaining in the distribution channel inventory at the end of the reporting period that we expect our customer to sell to wholesalers in future periods.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Government rebates&lt;/font&gt;: We are subject to discount obligations under government programs, including Medicaid programs and Medicare in the U.S. We estimate Medicaid and Medicare rebates based on a range of possible outcomes that are probability-weighted for the estimated payer mix. We record these reserves as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales in the same period we recognize the related sale. For Medicare rebates, we also estimate the number of patients in the prescription drug coverage gap for whom we will owe an additional liability under the Medicare Part D program. On a quarterly basis, we update our estimates and record any adjustments in the period that we identify the adjustments. In Germany, pharmaceutical companies must grant a specified rebate percentage to the German government. We include this rebate in the same period we recognize the related TEGSEDI product sales, resulting in a reduction of product sales.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Trade discounts and allowances: &lt;/font&gt;We provide customary invoice discounts on TEGSEDI product sales to our U.S. customer for prompt payment. We record this discount as a reduction of TEGSEDI product sales in the period in which we recognize the related product revenue. In addition, we receive and pay for various distribution services from our U.S. customer and wholesalers in our U.S. distribution channel. For services we receive that are either not distinct from the sale of TEGSEDI or for which we cannot reasonably estimate the fair value, we classify such fees as a reduction of TEGSEDI product sales.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Product Returns: &lt;/font&gt;Our U.S. customer has return rights and the wholesalers have limited return rights primarily related to the expiration date of the TEGSEDI product. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We estimate the amount of TEGSEDI product sales that our customer may return. We record our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale. Based on our distribution model for TEGSEDI, contractual inventory limits with our customer and wholesalers and the price of TEGSEDI, we believe we will have minimal returns. Our customer in Germany only takes title to the product once it receives an order from a hospital or pharmacy and therefore does not maintain any inventory of TEGSEDI, as such we do not estimate returns in Germany.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Other incentives: &lt;/font&gt;In the U.S., we estimate reserves for other incentives including co-payment assistance we provide to patients with commercial insurance who have coverage and reside in states that allow co-payment assistance. We record a reserve for the amount we estimate we will pay for co-payment assistance. We base our reserve on the number of estimated claims and our estimate of the cost per claim related to TEGSEDI product sales that we have recognized as revenue. We record our other incentive reserve estimates as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Research and development revenue under collaboration agreements:&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Upfront Payments&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;When we enter into a collaboration agreement with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&amp;amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&amp;amp;D services. For example, under our new &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;collaboration agreement with Roche to&lt;/font&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; develop IONIS-FB-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;for the treatment of complement-mediated diseases&lt;/font&gt;, we received a $75 million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our single performance obligation, R&amp;amp;D services. We are amortizing the $75 million upfront payment using an input method over the estimated period of time we are providing R&amp;amp;D services. Refer to &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Note 6, &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements&lt;/font&gt;, for further discussion. Under Topic 605, we amortized upfront payments evenly over the period of our obligation.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Milestone Payments&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are required to include additional consideration in the transaction price when it is probable. We typically include milestone payments for R&amp;amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because there is considerable uncertainty in the research and development processes that trigger these payments under our collaboration agreements. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales based milestone payments in the period we achieve the milestone under the sales-based royalty exception allowed under accounting rules.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For example, in the third quarter of 2017, we initiated a Phase 1/2a clinical study of IONIS-MAPT&lt;sub&gt;Rx &lt;/sub&gt;in patients with mild Alzheimer&amp;#8217;s disease. We earned a $10 million milestone payment from Biogen related to the initiation of this study. Under Topic 606, we added this payment to the transaction price and allocated it to our R&amp;amp;D services performance obligation. We are recognizing revenue from this milestone payment over our estimated period of performance. Under Topic 605, this milestone payment was recognized in full in the third quarter of 2017, which was the period in which we achieved the milestone event.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Conversely, we recognize in full those milestone payments that we earn based on our partners&amp;#8217; activities when our partner achieves the milestone event. For example, in the third quarter of 2018, we recognized a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of IONIS-AZ4-2.5-L&lt;sub&gt;Rx&lt;/sub&gt;. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We concluded that the milestone payment was not related to our R&amp;amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any performance obligations related to this milestone payment. &lt;/font&gt;Our revenue recognition of milestone payments we earn based on our partners&amp;#8217; activities did not change as a result of adopting Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;License Fees&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We generally recognize as revenue the total amount we determine to be the stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery. &lt;/font&gt;For example, in the fourth quarter of 2018, we earned a $35 million license fee when Biogen licensed IONIS-SOD1&lt;sub&gt;Rx&lt;/sub&gt; from us. Our recognition of license fees did not change as a result of adopting Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Amendments to Agreements&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the accounting for the amendment:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;If the goods and/or services are at a stand-alone selling price.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and at their stand-alone selling price, we then assess whether the remaining goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated revenue as a cumulative adjustment.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; for the prevention of thrombosis. As part of the agreement, Bayer paid us a $100 million upfront payment. At the onset of the agreement, we were responsible for completing a Phase 2 study of IONIS-FXI&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; and to initiate development of IONIS-FXI-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also eligible to receive milestone payments and tiered royalties on gross margins of IONIS-FXI&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; and IONIS-FXI-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of IONIS-FXI-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, to provide R&amp;amp;D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. &lt;/font&gt;Refer to &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Note 6, &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements&lt;/font&gt;, for further discussion &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;of our accounting treatment for our Bayer collaboration. &lt;/font&gt;Our allocation of the consideration we received for the Bayer amendment did not change as a result of adopting Topic 606. However, the method in which we are recognizing revenue related to our R&amp;amp;D services performance obligation did change. We are amortizing revenue related to our R&amp;amp;D services performance obligation using the input method under Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Multiple Agreements&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Whether the agreements were negotiated together with a single objective;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Whether the goods and/or services promised under the agreements are a single performance obligation.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance requires us to account for them as a combined arrangement.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: a new strategic neurology collaboration agreement and a stock purchase agreement, or SPA. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis. Refer to Note 6, &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; for further discussion of the accounting treatment for the 2018 strategic neurology collaboration with Biogen.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Contracts Receivable&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our contracts receivable balance represents the amounts we have billed our partners for goods we have delivered or services we have performed that are due to us unconditionally. When we bill our partners with payment terms based on the passage of time, we consider the contract receivable to be unconditional. We typically receive payment within one quarter of billing our partner&lt;/font&gt;. Our contracts receivable balance as of December 31, 2017 did not change when we adopted Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Unbilled SPINRAZA Royalties&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet. &lt;/font&gt;Our unbilled SPINRAZA royalties as of December 31, 2017 did not change when we adopted Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Deferred Revenue&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are often entitled to bill our customers and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.&lt;/font&gt; During the years ended December 31, 2018 and 2017, we recognized $105.3 million and $95.1 million of revenue from amounts that were in our beginning deferred revenue balances for those periods, respectively. Refer to our revenue recognition policy above detailing how we recognize revenue for further discussion.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the adjustments we were required to make to our deferred revenue amounts to adopt Topic 606 (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;At December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Current portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;106,465&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,871&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;125,336&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Long-term portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;72,708&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;35,318&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;108,026&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total deferred revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;179,173&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;54,189&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;233,362&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our deferred revenue balance increased $54.2 million at December 31, 2017 under Topic 606, compared to Topic 605. The increase was primarily related to the change in the accounting for certain milestone payments and the way in which we amortize payments. Under Topic 605, we previously recognized the majority of the milestone payments we earned in the period we achieved the milestone event, which did not impact our deferred revenue balance. Under Topic 606 we are now amortizing more milestone payments over the period of our performance obligation, which adds to our deferred revenue balance. Additionally, under Topic 605 we amortized payments evenly over the period of our obligation. Under Topic 606, we are required to use an input method to determine the amount we amortize each reporting period. The increase in deferred revenue relates to agreements with the following partners:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$24.2 million from Biogen;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$15.9 million from AstraZeneca;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$11.8 million from Novartis; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;div&gt;&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$ 2.3 million from other partners.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Cost of Products Sold&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We obtained the first regulatory approval for TEGSEDI in July 2018, as a result we began recognizing cost of products sold expenses related to TEGSEDI. Our cost of products sold includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the manufacturing and distribution of TEGSEDI. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of products sold. Prior to obtaining regulatory approval, we expensed a significant portion of the costs we incurred to produce the TEGSEDI supply we are using in the commercial launch as research and development expense.&amp;#160; &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We previously recognized $0.1 million of costs to produce TEGSEDI related to the TEGSEDI commercial revenue we recognized in 2018.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Research, Development and Patent Expenses&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our research and development expenses include wages, benefits, facilities, supplies, external services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development services prior to the services being rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2018, 2017 and 2016, research and development expenses were $411.9 million, $372.5 million and $340.4 million, respectively. A portion of the costs included in research and development expenses are costs associated with our partner agreements. For the years ended December 31, 2018, 2017 and 2016, research and development costs of approximately $58.7 million, $59.5 million and $187.1 million, respectively, were related to our partner agreements.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was 10.1 years at December 31, 2018.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The cost of our patents capitalized on our consolidated balance sheet at December 31, 2018 and 2017 was $32.7 million and $30.8 million, respectively. Accumulated amortization related to patents was $8.7 million and $8.8 million at December 31, 2018 and 2017, respectively.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ending December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amortization&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(in millions)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2019&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2020&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2021&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2022&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2023&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications that have future value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2018, 2017 and 2016, patent expenses were $2.6 million, $2.1 million and $3.9 million, respectively, and included non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $0.8 million, $0.4 million and $2.3 million, respectively.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Accrued Liabilities&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our accrued liabilities consisted of the following (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Clinical expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;22,125&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;16,347&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -18pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In-licensing expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;12,298&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;33,790&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -18pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Other miscellaneous expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;13,938&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;16,481&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total accrued liabilities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;48,361&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66,618&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Noncontrolling Interest in Akcea Therapeutics, Inc.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Prior to Akcea&amp;#8217;s IPO in July 2017, we owned 100 percent of Akcea. From the closing of Akcea&amp;#8217;s IPO in July 2017 through mid-April 2018, we owned approximately 68 percent&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;of Akcea. In the second, third and fourth quarters of 2018, we received additional shares of Akcea&amp;#8217;s stock related to our license of TEGSEDI and AKCEA-TTR-L&lt;sub&gt;Rx&lt;/sub&gt; to Akcea, increasing our ownership percentage to approximately 75 percent. We reflected this increase in our ownership percentage in these financial statements as an adjustment to noncontrolling interest. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The shares third parties own represent an interest in Akcea&amp;#8217;s equity that is not controlled by us. However, as we continue to maintain overall control of Akcea through our voting interest, we reflect the assets, liabilities and results of operations of Akcea in our consolidated financial statements. We reflect the noncontrolling interest attributable to other owners of Akcea&amp;#8217;s common stock in a separate line on the statement of operations and a separate line within stockholders&amp;#8217; equity in our consolidated balance sheet. In addition, we record a noncontrolling interest adjustment to account for the stock options Akcea grants, which if exercised, will dilute our ownership in Akcea. This adjustment is a reclassification within stockholders&amp;#8217; equity from additional paid-in capital to noncontrolling interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Concentration of Credit Risk&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents, short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&amp;#8217;s, Standard&amp;#160;&amp;amp; Poor&amp;#8217;s, or S&amp;amp;P, or Fitch, respectively. We have established guidelines relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Cash, Cash Equivalents and Short-Term Investments&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents. Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as &amp;#8220;available-for-sale&amp;#8221; and carry them at fair market value based upon prices on the last day of the fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments. We use the specific identification method to determine the cost of securities sold.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies that we received as part of a technology license or partner agreement. At December 31, 2018, we held equity investments in two publicly held companies, ProQR Therapeutics N.V., or ProQR, and Antisense Therapeutics Limited, or ATL. We also held equity investments in four privately-held companies, Atlantic Pharmaceuticals Limited, Dynacure SAS, Seventh Sense Biosystems and Suzhou Ribo Life Science Co, Ltd.&lt;/font&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In January 2018, we adopted the amended accounting guidance related to the recognition, measurement, presentation, and disclosure of certain financial instruments. The amended guidance requires us to measure and record our equity investments at fair value. Additionally, the amended accounting guidance requires us to recognize the changes in fair value in our consolidated statement of operations, instead of through accumulated other comprehensive income. Prior to 2018, we accounted for our equity investments in privately held companies under the cost method of accounting. Under the amended guidance we account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer. Our adoption of this guidance did not have an impact on our results.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Inventory Valuation&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We reflect our inventory on our consolidated balance sheet at the lower of cost or market value under the first-in, first-out method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials they have alternative future uses. We include in inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and, as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We expense these costs as R&amp;amp;D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency.&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We obtained the first regulatory approval for TEGSEDI in July 2018. At December 31, 2018, our physical inventory for TEGSEDI included API that we produced prior to when we obtained regulatory approval and accordingly has no cost basis as we had previously expensed the costs as R&amp;amp;D expenses.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development and historical write-offs. We did not record any inventory write-offs for the years ended December 31, 2018, 2017 or 2016. Total inventory was $8.6 million and $10.0 million as of December 31, 2018 and 2017, respectively.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Property, Plant and Equipment&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Estimated Useful Lives&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(in years)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Computer software, laboratory, manufacturing and other equipment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3 to 10&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;53,496&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66,558&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; 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width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Land improvements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div style="text-indent: -9pt; margin-left: 9pt; text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman',Times,serif;"&gt;20&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;132,160&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;121,907&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value of Financial Instruments&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable, accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Long-Lived Assets&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. We recorded charges of $0.8 million, $0.8 million and $2.3 million for the years ended December 31, 2018, 2017 and 2016, respectively, related primarily to the write-down of intangible assets.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Use of Estimates&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The preparation of consolidated financial statements in conformity with accounting principles generally accepted in the U.S. requires management to make estimates and assumptions that affect the amounts reported in the consolidated financial statements and accompanying notes. Actual results could differ from those estimates.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Stock-Based Compensation Expense&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We measure stock-based compensation expense for equity-classified awards, principally related to stock options, restricted stock units, or RSUs, and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the requisite service period in our Consolidated Statements of Operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We use the Black-Scholes model as our method of valuing option awards and stock purchase rights under our ESPP. On the grant date, we use our stock price and assumptions regarding a number of highly complex and subjective 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. Option-pricing models were developed for use in estimating the value of traded options that have no vesting or hedging restrictions and are fully transferable. Because our employee stock options have certain characteristics that are significantly different from traded options, and because changes in the subjective assumptions can materially affect the estimated value, in management&amp;#8217;s opinion, the existing valuation models may not provide an accurate measure of the fair value of our employee stock options. Although we determine the estimated fair value of employee stock options using an option-pricing model, that value may not be indicative of the fair value observed in a willing buyer/willing seller market transaction.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize compensation expense for option awards and RSUs 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;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The fair value of RSUs is based on the market price of our common stock on the date of grant.&amp;#160;The RSUs we have granted vest annually over a four-year period.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;See Note 4, &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Stockholders&amp;#8217; Equity,&lt;/font&gt; for additional information regarding our stock-based compensation plans.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Accumulated Other Comprehensive Loss&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated other comprehensive loss is primarily comprised of unrealized gains and losses on investments, net of taxes and adjustments we made to reclassify realized gains and losses on investments from other accumulated comprehensive loss to our Consolidated Statement of Operations. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2018, 2017 and 2016 (in thousands):&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Beginning balance accumulated other comprehensive loss&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(31,759&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(30,358&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(13,565&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Unrealized losses on securities, net of tax (1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(280&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(960&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(17,219&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Amounts reclassified from accumulated other comprehensive loss&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(374&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;447&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Currency translation adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;23&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(67&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(21&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net other comprehensive loss for the period&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(257&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,401&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(16,793&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ending balance accumulated other comprehensive loss&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(32,016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(31,759&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(30,358&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="display: inline-block; text-indent: 0px; font-size: 1px; width: 522pt;"&gt;&amp;#160;&lt;/font&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;A tax benefit of $0.3 million was included in other comprehensive loss for the year ended December 31, 2018. There was no tax benefit or expense for other comprehensive loss for the years ended December 31, 2017 or 2016.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Convertible Debt&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We account for convertible debt instruments, including our 1 percent and 2&amp;#190; percent notes that may be settled in cash upon conversion (including partial cash settlement) by separating the liability and equity components of the instruments in a manner that reflects our nonconvertible debt borrowing rate. We determine the carrying amount of the liability component by measuring the fair value of similar debt instruments that do not have the conversion feature. If no similar debt instrument exists, we estimate fair value by using assumptions that market participants would use in pricing a debt instrument, including market interest rates, credit standing, yield curves and volatilities. We use accounting estimates and assumptions when we determine the fair value of the debt component. These estimates and assumptions we use are judgmental in nature and could have a significant impact on the determination of the debt component, and the associated non-cash interest expense.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We assigned a value to the debt component of our convertible notes equal to the estimated fair value of similar debt instruments without the conversion feature, which resulted in us recording our debt at a discount. We are amortizing our debt issuance costs and debt discount over the life of the convertible notes as additional non-cash interest expense utilizing the effective interest method. For additional information, see Note 3, &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Long-Term Obligations and Commitments&lt;/font&gt;.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Segment Information&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have two operating segments, our Ionis Core segment and Akcea Therapeutics, our majority-owned affiliate. Akcea is &lt;/font&gt;a biopharmaceutical company focused on developing and commercializing medicines to treat patients with rare and serious diseases&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. We provide segment financial information and results for our Ionis Core segment and our Akcea Therapeutics segment based on the segregation of revenues and expenses that our chief decision maker reviews to assess operating performance and to make operating decisions. We allocate a portion of Ionis&amp;#8217; development, R&amp;amp;D support and general and administrative expenses to Akcea for work Ionis performs on behalf of Akcea.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Fair Value Measurements&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity securities in publicly-held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify the majority of our securities as Level 2. We obtain the fair value of our Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and comparing that fair value to the fair value based on observable market prices. During 2018 and 2017, there were no transfers between our Level 1 and Level 2 investments. When we recognize transfers between levels of the fair value hierarchy, we recognize the transfer on the date the event or change in circumstances that caused the transfer occurs.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following tables present the major security types we held at December 31, 2018 and 2017 that are regularly measured and carried at fair value. At December 31, 2018, our ProQR investment was &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;subject to trading restrictions through the fourth quarter of 2019, as a result we&lt;/font&gt; included a lack of marketability discount in valuing this investment, which is a Level 3 input. At December 31, 2017, we did not have any financial instruments that we valued using Level 3 inputs. The tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities&amp;#8217; fair value (in thousands):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;At&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quoted Prices in&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Active Markets&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Significant Other&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Observable Inputs&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Significant&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; Unobservable Inputs&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash equivalents (1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;146,281&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;146,281&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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font-family: 'Times New Roman', Times, serif;"&gt;1,349&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,017,298&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;406,435&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,609,514&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,349&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;At&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quoted Prices in&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Active Markets&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Significant Other&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Observable Inputs&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Level 2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash equivalents (1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;86,262&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;86,262&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Corporate debt securities (6)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;647,461&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;647,461&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by U.S. government agencies (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;136,325&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; 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width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by the U.S. Treasury (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;30,818&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;30,818&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (7)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;93,932&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;93,932&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;994,798&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;117,080&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;877,718&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div style="text-align: justify; text-indent: 500.1pt;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Included in cash and cash equivalents on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$50.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$14.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Included in other current assets on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(6)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$11.9 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(7)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$3.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Novartis Future Stock Purchase&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In January 2017, we and Akcea entered into a SPA with Novartis. As part of the SPA, Novartis was required to purchase $50 million of Akcea&amp;#8217;s common stock at the IPO price or our common stock at a premium if an IPO did not occur by April 2018. Therefore, at the inception of the SPA, we recorded a $5.0 million asset representing the fair value of the potential future premium we could have received if Novartis purchased our common stock. We determined the fair value of the future premium by calculating the value based on the stated premium in the SPA and estimating the probability of an Akcea IPO. We also included a &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;lack of marketability discount when we determined the fair value of the premium because we would have issued unregistered shares to Novartis if they had purchased our common stock. We measured this asset using Level 3 inputs and recorded it in other assets on our consolidated balance sheet. Because Akcea completed its IPO before April 2018, Novartis will not purchase additional shares of Ionis stock. Therefore, this asset no longer had any value and we wrote-off the remaining balance to other expenses on our third quarter 2017 consolidated statement of operations.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following is a reconciliation of the potential premium we would have received if Akcea had not completed its IPO, measured at fair value on a recurring basis using significant unobservable inputs (Level 3) for 2017 (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Beginning balance of Level 3 instruments&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Value of the potential premium we will receive from Novartis at inception of the SPA (January 2017)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5,035&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Write-off of premium to other expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,035&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ending balance of Level 3 instruments&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Income Taxes&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development credit carryforwards. We record a valuation allowance when necessary to reduce deferred tax assets to the amount we expect to realize.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes. Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for income taxes in the period in which such determination is made.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted.&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be realized.&amp;#160;&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For U.S. federal income tax purposes, we are required to file separate U.S. federal income tax returns for Ionis and Akcea. We began deconsolidating Akcea for U.S. federal income tax purposes upon Akcea&amp;#8217;s initial public offering. As a result, we are required to assess our Ionis stand-alone and Akcea&amp;#8217;s valuation allowances separately even though we consolidate Akcea&amp;#8217;s financial results in our consolidated financial statements. We continue to file combined state tax returns in most jurisdictions. As a result, we continue to assess the state portion of our valuation allowance for those jurisdictions on a consolidated basis.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have historically recorded a valuation allowance against all our net deferred tax assets due to cumulative financial statement losses. However, in the fourth quarter of 2018, we reversed the valuation allowance previously recorded against our Ionis stand-alone U.S. federal net deferred tax assets, resulting in a one-time non-cash tax benefit of $332.1 million. Given our current stand-alone Ionis pre-tax income, and assuming we maintain this current level of Ionis stand-alone pre-tax income, we expect to generate income before taxes in the U.S. in future periods at a level that would result in us fully utilizing our U.S. federal net operating loss carryforwards and most of our Research and Development and Orphan Drug tax credit carryforwards over the next three years.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We continue to maintain a full valuation allowance of $234.2 million against all of Akcea&amp;#8217;s net deferred tax assets and the net state deferred tax assets of Ionis at December 31, 2018 due to uncertainties related to our ability to realize the tax benefits associated with these assets.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Impact of Recently Issued Accounting Standards&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In February 2016, the FASB issued amended accounting guidance related to lease accounting, which will require us to record all leases with a term longer than one year on our balance sheet. When we record leases on our balance sheet under the new guidance, we will record a liability with a value equal to the present value of payments we will make over the life of the lease (lease liability) and an asset representing the underlying leased asset (right of use asset). The new accounting guidance requires us to determine if our leases are operating or financing leases. We will record expense for operating leases on a straight-line basis as an operating expense. If we determine a lease is a financing&amp;#160;lease, we will record both interest and amortization expense and generally the expense will be higher in the earlier periods of the lease. We adopted this guidance on January 1, 2019 and adjusted our opening balance sheet on that date. We elected the available practical expedients. The most significant impact was the recognition of right of use assets and lease liabilities for our operating leases. We are in the process of finalizing the impact of the adoption. The adoption will not have an impact on our consolidated statement of operations or statement of cash flows.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In June 2016, the FASB issued guidance that changes the measurement of credit losses for most financial assets and certain other instruments. If we have credit losses, this updated guidance requires us to record allowances for these instruments under a new expected credit loss model. This model requires us to estimate the expected credit loss of an instrument over its lifetime, which represents the portion of the amortized cost basis we do not expect to collect. The new guidance requires us to remeasure our allowance in each reporting period we have credit losses. The new standard is effective for annual and interim periods beginning after December 15, 2019. Early adoption is permitted for periods beginning after December 15, 2018. When we adopt the new standard, we will make any adjustments to beginning balances through a cumulative-effect adjustment to accumulated deficit on that date. We plan to adopt this guidance on January 1, 2020. We are currently assessing the effects it will have on our consolidated financial statements and disclosures.&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In February 2018, the FASB issued updated guidance for reclassification of tax effects from accumulated other comprehensive income (loss). The updated guidance gives entities an option to reclassify amounts included in accumulated other comprehensive income (loss) that under the Tax Act do not have a way to be relieved, and allows a one-time reclassification to retained earnings. The updated guidance is effective for all entities for fiscal years beginning after December 31, 2018, and interim periods within those fiscal years. We have decided not to record the reclassification adjustments provided by this guidance.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In June 2018, the FASB issued updated guidance to simplify the accounting for stock-based compensation expense for nonemployees. Specifically, we are now expensing grants to nonemployees in a similar manner as grants to employees. Previously, we had to re-value these grants at each reporting period to reflect the current fair value. Under the amended guidance, we value grants to nonemployees when we grant them and we will not adjust their value for future changes. We adopted this guidance in the second quarter of 2018. The updated guidance did not have a material impact to our financial results.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In November 2018, the FASB issued clarifying guidance of the interaction between the collaboration accounting guidance and the new revenue recognition guidance we adopted on January 1, 2018 (Topic 606). The clarifying guidance included the following:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;When a participant is considered a customer in a collaborative arrangement, all of the associated accounting under Topic 606 should be applied;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Adds &amp;#8220;unit of account&amp;#8221; concept to collaboration accounting guidance to align with Topic 606. This is used to determine if revenue is recognized or if a contra expense is recognized from consideration received under a collaboration; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Precludes revenue from being recognized under Topic 606 when a transaction with a collaborative partner is determined not be a customer and is not directly related to the sales to third parties.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The updated guidance is effective for public entities for fiscal years beginning after December 15, 2019, and interim periods within those fiscal years. Early adoption is permitted. We plan to adopt this guidance on January 1, 2020. We are currently assessing the effects it will have on our consolidated financial statements and disclosures.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:OrganizationConsolidationBasisOfPresentationBusinessDescriptionAndAccountingPoliciesTextBlock>
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  <us-gaap:ProfitLoss contextRef="c20170701to20170930" unitRef="U001" decimals="-3">-7493000</us-gaap:ProfitLoss>
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  <us-gaap:PropertyPlantAndEquipmentUsefulLife contextRef="c20180101to20181231_PropertyPlantAndEquipmentByTypeAxis_FurnitureAndFixturesMember_RangeAxis_MinimumMember">P5Y</us-gaap:PropertyPlantAndEquipmentUsefulLife>
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  <!--Property, Plant and Equipment, Gross-Equipment and Computer Software [Member]-->
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  <us-gaap:PropertyPlantAndEquipmentGross contextRef="c20181231_PropertyPlantAndEquipmentByTypeAxis_EquipmentAndComputerSoftwareMember" unitRef="U001" decimals="-3">53496000</us-gaap:PropertyPlantAndEquipmentGross>
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  <us-gaap:PropertyPlantAndEquipmentGross contextRef="c20171231_PropertyPlantAndEquipmentByTypeAxis_LeaseholdImprovementsMember" unitRef="U001" decimals="-3">26748000</us-gaap:PropertyPlantAndEquipmentGross>
  <!--Property, Plant and Equipment, Gross-Land [Member]-->
  <us-gaap:PropertyPlantAndEquipmentGross contextRef="c20181231_PropertyPlantAndEquipmentByTypeAxis_LandMember" unitRef="U001" decimals="-3">14493000</us-gaap:PropertyPlantAndEquipmentGross>
  <!--Property, Plant and Equipment, Gross-Land Improvements [Member]-->
  <us-gaap:PropertyPlantAndEquipmentGross contextRef="c20171231_PropertyPlantAndEquipmentByTypeAxis_LandImprovementsMember" unitRef="U001" decimals="-3">2853000</us-gaap:PropertyPlantAndEquipmentGross>
  <!--Property, Plant and Equipment, Gross-Furniture and Fixtures [Member]-->
  <us-gaap:PropertyPlantAndEquipmentGross contextRef="c20181231_PropertyPlantAndEquipmentByTypeAxis_FurnitureAndFixturesMember" unitRef="U001" decimals="-3">6283000</us-gaap:PropertyPlantAndEquipmentGross>
  <!--Property, Plant and Equipment, Gross-Property, Plant and Equipment, Excluding Land [Member]-->
  <us-gaap:PropertyPlantAndEquipmentGross contextRef="c20171231_PropertyPlantAndEquipmentByTypeAxis_PropertyPlantAndEquipmentExcludingLandMember" unitRef="U001" decimals="-3">195090000</us-gaap:PropertyPlantAndEquipmentGross>
  <!--Property, Plant and Equipment, Gross-Furniture and Fixtures [Member]-->
  <us-gaap:PropertyPlantAndEquipmentGross contextRef="c20171231_PropertyPlantAndEquipmentByTypeAxis_FurnitureAndFixturesMember" unitRef="U001" decimals="-3">6161000</us-gaap:PropertyPlantAndEquipmentGross>
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font-weight: bold;"&gt;Estimated Useful Lives&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(in years)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Computer software, laboratory, manufacturing and other equipment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3 to 10&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;53,496&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66,558&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Building, building improvements and building systems&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;15 to 40&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;97,528&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;92,770&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Land improvements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div style="text-indent: -9pt; margin-left: 9pt; text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman',Times,serif;"&gt;20&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,853&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,853&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Leasehold improvements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5 to 15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,981&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,748&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;195,090&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Less accumulated depreciation&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; 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font-family: 'Times New Roman', Times, serif;"&gt;121,907&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:PropertyPlantAndEquipmentTextBlock>
  <!--Property, Plant and Equipment, Policy [Policy Text Block]-->
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padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(in years)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66,558&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; 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width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Land improvements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div style="text-indent: -9pt; margin-left: 9pt; text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman',Times,serif;"&gt;20&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;132,160&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;121,907&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:PropertyPlantAndEquipmentPolicyTextBlock>
  <!--Property, Plant and Equipment, Net-->
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  <!--Property, Plant and Equipment, Net-->
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  <!--Property, Plant and Equipment, Net-Property, Plant and Equipment, Excluding Land [Member]-->
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  <!--Property, Plant and Equipment, Net-Property, Plant and Equipment, Excluding Land [Member]-->
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  <!--Quarterly Financial Information [Text Block]-->
  <us-gaap:QuarterlyFinancialInformationTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;10. Quarterly Financial Data (Unaudited)&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following financial information reflects all normal recurring adjustments, which are, in the opinion of management, necessary for a fair statement of the results of the interim periods. Summarized quarterly data for the years ended December 31, 2018 and 2017 are as follows (in thousands, except per share data).&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2018 Quarters&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;First&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quarter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Second&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quarter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Third&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quarter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Fourth&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quarter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;144,419&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;117,747&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;145,395&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;192,113&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Operating expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;147,720&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;168,028&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;163,967&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;181,331&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(50,281&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(20,365&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,420&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;"&gt;(4,559&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;320,078&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.29&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3,085&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(7,493&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(9,169&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss) attributable to Ionis Pharmaceutical, Inc. common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2,922&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income (loss) per share (1) (2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.02&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.02&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Diluted net income (loss) per share (1) (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.02&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.02&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div style="text-align: justify; text-indent: 500.1pt;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We computed net income (loss) per share independently for each of the quarters presented. Therefore, the sum of the quarterly net income (loss) per share will not necessarily equal the total for the year.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;As discussed in Note 1, &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Organization and Significant Accounting Policies, &lt;/font&gt;we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income (loss) per share calculation for each of the quarters in 2018 and for the third and fourth quarters of 2017 considered our net income for Ionis on a stand-alone basis plus our share of Akcea&amp;#8217;s net loss for the period. To calculate the portion of Akcea&amp;#8217;s net loss attributable to our ownership, we multiplied Akcea&amp;#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our&amp;#160;total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our basic net income (loss) per share for each quarter in 2018 was calculated as follows (in thousands, except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended March 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Income (Loss)&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; Portion of&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;45,448&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.44&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(19,997&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(19,997&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; 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vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended June 30, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended September 30, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;43,226&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net loss available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4,563&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net loss per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.79&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(53,219&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(53,219&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;372,913&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;319,694&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;137,699&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.32&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Prior to Akcea&amp;#8217;s IPO in July 2017, we owned Akcea series A convertible preferred stock, which included a six percent cumulative dividend. Upon completion of Akcea&amp;#8217;s IPO in July 2017, our preferred stock was converted into common stock on a 1:1 basis. The preferred stock dividend was not paid at the IPO because the IPO was not a liquidation event or a change in control. During the three months ended September 30, 2017, Akcea used a two-class method to compute its net income (loss) per share because it had both common and preferred shares outstanding during the periods. The two-class method required Akcea to calculate its net income (loss) per share&amp;#160;for each class of stock by dividing total distributable losses applicable to preferred and common stock, including the&amp;#160;six percent&amp;#160;cumulative dividend contractually due to series A convertible preferred shareholders, by the weighted-average of preferred and common shares outstanding during the requisite period. Since Akcea used the two-class method, accounting rules required us to include our portion of Akcea&amp;#8217;s net income (loss) per share for both Akcea&amp;#8217;s common and preferred shares that we owned in our calculation of basic and diluted net income (loss) per share for the three months ended September 30, 2017.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our basic net income (loss) per share for the three months ended &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;September 30, 2017&lt;/font&gt; was calculated as follows (in thousands, except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended September 30, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Loss&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Portion of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;36,556&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; 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width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,063&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Preferred shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5,651&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.01&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(57&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,120&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; 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text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10,144&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net loss available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,976&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,370&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net loss per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.02&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: justify; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our basic net income (loss) per share for the three months ended &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 30, 2017&lt;/font&gt; was calculated as follows (in thousands, except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Loss&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Portion of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;45,448&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.30&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(13,634&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(13,634&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10,510&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net loss available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3,124&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,818&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net loss per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For the three months ended December 31, 2018, we had net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods. Diluted common equivalent shares for the three months ended December 31, 2018 consisted of the following (in thousands except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Income&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Numerator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Denominator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per-Share&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;319,694&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;137,699&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.32&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effect of dilutive securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon exercise of stock options&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,254&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon restricted stock award issuance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;636&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our ESPP&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our 1 percent convertible notes&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10,745&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10,260&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income available to Ionis common stockholders, plus assumed conversions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;330,439&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;149,856&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.21&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For the three months ended March 31, 2017, we owned 100 percent of Akcea. As a result, we did not have to adjust our earnings per share calculation. For the three months ended March 31, 2017, we had net income. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods. Diluted common equivalent shares for the three months ended March 31, 2017 consisted of the following (in thousands except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended March 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Income&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Numerator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Denominator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per-Share&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,964&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;122,861&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effect of dilutive securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon exercise of stock options&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,674&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon restricted stock award issuance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;377&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our ESPP&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;60&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,964&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,972&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For the three months ended March 31, 2017, the calculation excluded the 1 percent and 2&amp;#190; percent notes because the effect on diluted earnings per share was anti-dilutive.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:QuarterlyFinancialInformationTextBlock>
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  <!--Revenue Recognition, Policy [Policy Text Block]-->
  <us-gaap:RevenueRecognitionPolicyTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Revenue Recognition&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Adoption of New Revenue Recognition Accounting Standard (Topic 606)&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In May 2014, the FASB issued accounting guidance on the recognition of revenue from customers. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;This guidance supersedes the revenue recognition requirements we previously followed in Accounting Standards Codification, or ASC, Topic 605, &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Revenue Recognition&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, or Topic 605, and created a new Topic 606, &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Revenue from Contracts with Customers&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, or Topic 606. &lt;/font&gt;Under Topic 606, an entity will recognize revenue when it transfers control of promised goods or services to customers in an amount that reflects what the entity expects to receive in exchange for the goods or services. Further, an entity will recognize revenue upon satisfying the performance obligation(s) under the related contract. We adopted Topic 606 on January 1, 2018 under the full retrospective approach, which required us to revise our prior period revenue. Under Topic 606, we were required to review all of our ongoing collaboration agreements in which we recognized revenue after January 1, 2016. We were required to assess what our revenue would have been for the period from January 1, 2016 to December 31, 2017 under Topic 606. As a result of this analysis, we determined that the cumulative revenue we would have recognized under Topic 606 decreased by $86.1 million. We recorded this amount as a cumulative adjustment to our accumulated deficit as of January 1, 2016 on our revised statement of stockholders&amp;#8217; equity. We have labeled our prior period financial statements &amp;#8220;as revised&amp;#8221; to indicate the change required under the accounting rules.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following tables summarize the adjustments we were required to make to amounts we originally reported in 2017 and 2016 to adopt Topic 606 (in thousands, except per share amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Consolidated Balance Sheet&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;At December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Current portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;106,465&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,871&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;125,336&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Long-term portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;9,519&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7,474&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;122,059&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120,014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Research and development revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;385,607&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,558&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;394,165&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;507,666&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;514,179&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;24,534&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;31,047&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(17,296&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(10,783&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,970&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,316&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;346&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income per share, basic and diluted&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.08&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Revenue:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Commercial revenue:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;SPINRAZA royalties&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;883&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;883&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;19,839&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21,884&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;20,722&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;22,767&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Research and development revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;325,898&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;24,111&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;350,009&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;346,620&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;372,776&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income (loss) from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; 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text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(60,400&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(60,400&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss) per share, basic and diluted&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.72&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.22&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.50&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Consolidated Statements of Cash Flows&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(17,296&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(10,783&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27.15pt; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;36,695&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;30,182&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at beginning of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at end of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;129,630&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;129,630&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(86,556&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(60,400&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27.15pt; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(59,150&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(85,306&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at beginning of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;128,797&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;128,797&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at end of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Under Topic 606, compared to Topic 605, our total revenue increased $6.5 million for &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2017&lt;/font&gt; and $26.2 million for &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2016&lt;/font&gt;. The change in our revenue was primarily due to:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;A change in how we recognize milestone payments:&lt;/u&gt;&lt;/font&gt; Topic 606 requires us to amortize more of the milestone payments we achieve, rather than recognizing the milestone payments in full in the period in which we achieved the milestone event as we did under Topic 605. This change resulted in an increase in R&amp;amp;D revenue recognized for 2017 and 2016 of $23.7 million and $24.1 million, respectively.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;A change in how we calculate revenue for payments we are recognizing into revenue over time:&lt;/u&gt;&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; Under Topic 605, we amortized payments into revenue evenly over the period of our obligations. When we made a change to our estimated completion period, we recognized that change on a prospective basis. Under Topic 606, we are required to use an input method to determine the amount we amortize each reporting period. Each period we review our &amp;#8220;inputs&amp;#8221; such as our level of effort expended, including the time we estimate it will take us to complete the activities or costs incurred, relative to the total expected inputs to satisfy the performance obligation. For certain collaborations, such as Bayer and Novartis, the input method resulted in a change to the revenue we had previously recognized using a straight-line amortization method.&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;This change resulted in a decrease in our R&amp;amp;D revenue of $15.1 million for 2017. This change did not result in an impact to our 2016 R&amp;amp;D revenue.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our updated revenue recognition policy reflecting Topic 606 is as follows:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Our Revenue Sources&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue, we include the amounts in deferred revenue on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as commercial revenue future sales milestone payments and royalties we earn under our partnerships.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Commercial Revenue: TEGSEDI Product Sales, net&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We began adding product sales from TEGSEDI to our commercial revenue in the fourth quarter of 2018. &lt;/font&gt;In the U.S., TEGSEDI is distributed through an exclusive distribution agreement with a third-party logistics company, or 3PL, that takes title to TEGSEDI. The 3PL is our sole customer in the U.S. The 3PL then distributes TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distribute TEGSEDI to health care providers and patients. In Germany, TEGSEDI is distributed through a non-exclusive distribution model with a 3PL that takes title to TEGSEDI. The 3PL is our sole customer in Germany. The 3PL in Germany then distributes TEGSEDI to hospitals and pharmacies.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Research and development revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;amp;D, services, and manufacturing services.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our collaboration agreements are detailed in Note 6, &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements.&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;&amp;#160;&lt;/font&gt;Under each collaboration note we discuss our specific revenue recognition conclusions, including our significant performance obligations under each collaboration.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Steps to Recognize Revenue&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We use a five step process to determine the amount of revenue we should recognize and when we should recognize it. The five step process is as follows:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;1.&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Identify the contract&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the following criteria:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We and our partner approved the contract and we are both committed to perform our obligations;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have identified our rights, our partner&amp;#8217;s rights and the payment terms;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the contract; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We believe collectability is probable.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="margin-bottom: 10pt;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;2.&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Identify the performance obligations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We next identify the distinct goods and services we are required to provide under the contract. Accounting rules refer to these as our performance obligations. We typically have only one performance obligation at the inception of a contract, which is to perform R&amp;amp;D services.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Often times we enter into a collaboration agreement in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights. These items are contingent upon future events that may not occur. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;3.&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Determine the transaction price&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because the payments are not probable. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and are usually based on scientific progress. For example, in the first quarter of 2019, we earned a $35 million milestone payment from Roche when it dosed the first patient in the Phase 3 study of IONIS-HTT&lt;sub&gt;Rx&lt;/sub&gt;.&amp;#160; At December 31, 2018, we determined it was not probable that we could earn this milestone payment.&amp;#160;As such, we did not recognize any revenue associated with it in 2018.&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;&amp;#160; &amp;#160;&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;4.&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Allocate the transaction price&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling price.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement. We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected income to present value. The significant inputs we use to determine the projected income of a license could include:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Estimated future product sales;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Estimated royalties on future product sales;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Contractual milestone payments;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expenses we expect to incur;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income taxes; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;A discount rate.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We typically estimate the selling price of R&amp;amp;D services by using our internal estimates of the cost to perform the specific services. The significant inputs we use to determine the selling price of our R&amp;amp;D services include:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The number of internal hours we estimate we will spend performing these services;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The estimated cost of work we will perform;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The estimated cost of work that we will contract with third parties to perform; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The estimated cost of API we will use.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For purposes of determining the stand-alone selling price of the R&amp;amp;D services we perform and the API we will deliver, accounting guidance requires us to include a markup for a reasonable profit margin.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;5.&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Recognize revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;amp;D services. We recognize revenue at a point in time when our partner receives full use of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For R&amp;amp;D services that we recognize over time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;change over the course of the collaboration, they may affect the timing and amount of revenue that we recognize in the current and future periods.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following are examples of when we typically recognize revenue based on the types of payments we receive.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize royalty revenue in the period in which the counterparty sells the related product, which in certain cases may require us to estimate our royalty revenue. &lt;/font&gt;We recognize royalties from SPINRAZA sales in the period Biogen records the sale of SPINRAZA. Our accounting for SPINRAZA royalties did not change as a result of adopting Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Commercial Revenue: TEGSEDI Product Sales, net&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize TEGSEDI product sales in the period &lt;/font&gt;when our customer obtains control of TEGSEDI, which occurs at a point in time upon transfer of title to the customer. We classify payments to customers or other parties in the distribution channel for services that are distinct and priced at fair value as selling, general and administrative expenses in our consolidated statements of operations. Otherwise payments to customers or other parties in the distribution channel that do not meet those criteria are classified as a reduction of revenue, as discussed further below. We exclude from revenues, taxes collected from customers relating to product sales and remitted to governmental authorities.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Reserves for TEGSEDI Product Sales&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We record TEGSEDI product sales at our net sales price, or transaction price. We include in our transaction price estimated reserves for discounts, returns, chargebacks, rebates, co-pay assistance and other allowances that we offer within contracts between us and our customers, wholesalers, health care providers and other indirect customers. We estimate our reserves using the amounts we have earned or what we can claim on the associated sales. We classify our reserves as reductions of accounts receivable when the amount is payable to our customer or a current liability when the amount is payable to a party other than our customer in our consolidated balance sheet. In certain cases, our estimates include a range of possible outcomes that are probability-weighted for relevant factors such as our historical experience, current contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflect our best estimates under the terms of our respective contracts. When calculating our reserves and related product sales, we only recognize amounts to the extent that we consider it probable that we would not have to reverse in a future period a significant amount of the cumulative sales we previously recognized. The actual amounts we receive may ultimately differ from our reserve estimates. If actual amounts in the future vary from our estimates, we will adjust these estimates, which would affect our net TEGSEDI product sales in the respective period.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following are the components of variable consideration related to TEGSEDI product sales:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Chargebacks: &lt;/font&gt;In the U.S., we estimate obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charges us for the difference between what it pays for the product and the selling price to the qualified healthcare providers. We record reserves for these chargebacks related to TEGSEDI product sales to our U.S. customer during the reporting period. We also estimate the amount of product remaining in the distribution channel inventory at the end of the reporting period that we expect our customer to sell to wholesalers in future periods.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Government rebates&lt;/font&gt;: We are subject to discount obligations under government programs, including Medicaid programs and Medicare in the U.S. We estimate Medicaid and Medicare rebates based on a range of possible outcomes that are probability-weighted for the estimated payer mix. We record these reserves as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales in the same period we recognize the related sale. For Medicare rebates, we also estimate the number of patients in the prescription drug coverage gap for whom we will owe an additional liability under the Medicare Part D program. On a quarterly basis, we update our estimates and record any adjustments in the period that we identify the adjustments. In Germany, pharmaceutical companies must grant a specified rebate percentage to the German government. We include this rebate in the same period we recognize the related TEGSEDI product sales, resulting in a reduction of product sales.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Trade discounts and allowances: &lt;/font&gt;We provide customary invoice discounts on TEGSEDI product sales to our U.S. customer for prompt payment. We record this discount as a reduction of TEGSEDI product sales in the period in which we recognize the related product revenue. In addition, we receive and pay for various distribution services from our U.S. customer and wholesalers in our U.S. distribution channel. For services we receive that are either not distinct from the sale of TEGSEDI or for which we cannot reasonably estimate the fair value, we classify such fees as a reduction of TEGSEDI product sales.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Product Returns: &lt;/font&gt;Our U.S. customer has return rights and the wholesalers have limited return rights primarily related to the expiration date of the TEGSEDI product. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We estimate the amount of TEGSEDI product sales that our customer may return. We record our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale. Based on our distribution model for TEGSEDI, contractual inventory limits with our customer and wholesalers and the price of TEGSEDI, we believe we will have minimal returns. Our customer in Germany only takes title to the product once it receives an order from a hospital or pharmacy and therefore does not maintain any inventory of TEGSEDI, as such we do not estimate returns in Germany.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Other incentives: &lt;/font&gt;In the U.S., we estimate reserves for other incentives including co-payment assistance we provide to patients with commercial insurance who have coverage and reside in states that allow co-payment assistance. We record a reserve for the amount we estimate we will pay for co-payment assistance. We base our reserve on the number of estimated claims and our estimate of the cost per claim related to TEGSEDI product sales that we have recognized as revenue. We record our other incentive reserve estimates as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Research and development revenue under collaboration agreements:&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Upfront Payments&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;When we enter into a collaboration agreement with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&amp;amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&amp;amp;D services. For example, under our new &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;collaboration agreement with Roche to&lt;/font&gt;&lt;font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; develop IONIS-FB-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;for the treatment of complement-mediated diseases&lt;/font&gt;, we received a $75 million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our single performance obligation, R&amp;amp;D services. We are amortizing the $75 million upfront payment using an input method over the estimated period of time we are providing R&amp;amp;D services. Refer to &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Note 6, &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements&lt;/font&gt;, for further discussion. Under Topic 605, we amortized upfront payments evenly over the period of our obligation.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;Milestone Payments&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are required to include additional consideration in the transaction price when it is probable. We typically include milestone payments for R&amp;amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because there is considerable uncertainty in the research and development processes that trigger these payments under our collaboration agreements. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales based milestone payments in the period we achieve the milestone under the sales-based royalty exception allowed under accounting rules.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For example, in the third quarter of 2017, we initiated a Phase 1/2a clinical study of IONIS-MAPT&lt;sub&gt;Rx &lt;/sub&gt;in patients with mild Alzheimer&amp;#8217;s disease. We earned a $10 million milestone payment from Biogen related to the initiation of this study. Under Topic 606, we added this payment to the transaction price and allocated it to our R&amp;amp;D services performance obligation. We are recognizing revenue from this milestone payment over our estimated period of performance. Under Topic 605, this milestone payment was recognized in full in the third quarter of 2017, which was the period in which we achieved the milestone event.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Conversely, we recognize in full those milestone payments that we earn based on our partners&amp;#8217; activities when our partner achieves the milestone event. For example, in the third quarter of 2018, we recognized a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of IONIS-AZ4-2.5-L&lt;sub&gt;Rx&lt;/sub&gt;. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We concluded that the milestone payment was not related to our R&amp;amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any performance obligations related to this milestone payment. &lt;/font&gt;Our revenue recognition of milestone payments we earn based on our partners&amp;#8217; activities did not change as a result of adopting Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;u&gt;License Fees&lt;/u&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We generally recognize as revenue the total amount we determine to be the stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery. &lt;/font&gt;For example, in the fourth quarter of 2018, we earned a $35 million license fee when Biogen licensed IONIS-SOD1&lt;sub&gt;Rx&lt;/sub&gt; from us. Our recognition of license fees did not change as a result of adopting Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Amendments to Agreements&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the accounting for the amendment:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;If the goods and/or services are at a stand-alone selling price.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and at their stand-alone selling price, we then assess whether the remaining goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated revenue as a cumulative adjustment.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; for the prevention of thrombosis. As part of the agreement, Bayer paid us a $100 million upfront payment. At the onset of the agreement, we were responsible for completing a Phase 2 study of IONIS-FXI&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; and to initiate development of IONIS-FXI-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also eligible to receive milestone payments and tiered royalties on gross margins of IONIS-FXI&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; and IONIS-FXI-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of IONIS-FXI-L&lt;/font&gt;&lt;sub&gt;Rx&lt;/sub&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;, to provide R&amp;amp;D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. &lt;/font&gt;Refer to &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Note 6, &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements&lt;/font&gt;, for further discussion &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;of our accounting treatment for our Bayer collaboration. &lt;/font&gt;Our allocation of the consideration we received for the Bayer amendment did not change as a result of adopting Topic 606. However, the method in which we are recognizing revenue related to our R&amp;amp;D services performance obligation did change. We are amortizing revenue related to our R&amp;amp;D services performance obligation using the input method under Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Multiple Agreements&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Whether the agreements were negotiated together with a single objective;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Whether the goods and/or services promised under the agreements are a single performance obligation.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance requires us to account for them as a combined arrangement.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: a new strategic neurology collaboration agreement and a stock purchase agreement, or SPA. &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis. Refer to Note 6, &lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Collaborative Arrangements and Licensing Agreements&lt;/font&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; for further discussion of the accounting treatment for the 2018 strategic neurology collaboration with Biogen.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Contracts Receivable&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our contracts receivable balance represents the amounts we have billed our partners for goods we have delivered or services we have performed that are due to us unconditionally. When we bill our partners with payment terms based on the passage of time, we consider the contract receivable to be unconditional. We typically receive payment within one quarter of billing our partner&lt;/font&gt;. Our contracts receivable balance as of December 31, 2017 did not change when we adopted Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Unbilled SPINRAZA Royalties&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet. &lt;/font&gt;Our unbilled SPINRAZA royalties as of December 31, 2017 did not change when we adopted Topic 606.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Deferred Revenue&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are often entitled to bill our customers and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.&lt;/font&gt; During the years ended December 31, 2018 and 2017, we recognized $105.3 million and $95.1 million of revenue from amounts that were in our beginning deferred revenue balances for those periods, respectively. Refer to our revenue recognition policy above detailing how we recognize revenue for further discussion.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the adjustments we were required to make to our deferred revenue amounts to adopt Topic 606 (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;At December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Current portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;106,465&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,871&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;125,336&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Long-term portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;72,708&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;35,318&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;108,026&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total deferred revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;179,173&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;54,189&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;233,362&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our deferred revenue balance increased $54.2 million at December 31, 2017 under Topic 606, compared to Topic 605. The increase was primarily related to the change in the accounting for certain milestone payments and the way in which we amortize payments. Under Topic 605, we previously recognized the majority of the milestone payments we earned in the period we achieved the milestone event, which did not impact our deferred revenue balance. Under Topic 606 we are now amortizing more milestone payments over the period of our performance obligation, which adds to our deferred revenue balance. Additionally, under Topic 605 we amortized payments evenly over the period of our obligation. Under Topic 606, we are required to use an input method to determine the amount we amortize each reporting period. The increase in deferred revenue relates to agreements with the following partners:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$24.2 million from Biogen;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$15.9 million from AstraZeneca;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$11.8 million from Novartis; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;div&gt;&lt;table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$ 2.3 million from other partners.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:RevenueRecognitionPolicyTextBlock>
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  <us-gaap:ScheduleofFiniteLivedIntangibleAssetsFutureAmortizationExpenseTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ending December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amortization&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(in millions)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2019&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2020&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2021&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2022&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2023&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleofFiniteLivedIntangibleAssetsFutureAmortizationExpenseTableTextBlock>
  <!--Percentage ownership before IPO-Akcea Therapeutics, Inc. [Member]-->
  <us-gaap:SaleOfStockPercentageOfOwnershipBeforeTransaction contextRef="c20170101to20170630_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U003" decimals="INF">1</us-gaap:SaleOfStockPercentageOfOwnershipBeforeTransaction>
  <!--Percentage ownership before IPO-Akcea Therapeutics, Inc. [Member]-->
  <us-gaap:SaleOfStockPercentageOfOwnershipBeforeTransaction contextRef="c20160101to20161231_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U003" decimals="INF">1</us-gaap:SaleOfStockPercentageOfOwnershipBeforeTransaction>
  <!--Percentage ownership before IPO-Akcea Therapeutics, Inc. [Member]-->
  <us-gaap:SaleOfStockPercentageOfOwnershipBeforeTransaction contextRef="c20170101to20170331_OwnershipAxis_AkceaTherapeuticsIncMember" unitRef="U003" decimals="INF">1</us-gaap:SaleOfStockPercentageOfOwnershipBeforeTransaction>
  <!--Quarterly Financial Information [Table Text Block]-->
  <us-gaap:ScheduleOfQuarterlyFinancialInformationTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following financial information reflects all normal recurring adjustments, which are, in the opinion of management, necessary for a fair statement of the results of the interim periods. Summarized quarterly data for the years ended December 31, 2018 and 2017 are as follows (in thousands, except per share data).&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2018 Quarters&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;First&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quarter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Second&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quarter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Third&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quarter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Fourth&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Quarter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;144,419&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;117,747&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;145,395&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;192,113&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Operating expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;147,720&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;168,028&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;163,967&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;181,331&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income (loss) from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3,301&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(50,281&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(18,572&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(20,365&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,420&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(40,358&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4,559&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;320,078&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income (loss) per share (1) (2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.01&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.29&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.32&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Diluted net income (loss) per share (1) (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.01&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.29&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;115,800&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;"&gt;173,992&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income (loss) from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11,312&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(6,200&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,964&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3,085&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(7,493&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(9,169&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss) attributable to Ionis Pharmaceutical, Inc. common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,964&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3,085&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2,611&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2,922&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income (loss) per share (1) (2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.02&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.02&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Diluted net income (loss) per share (1) (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.02&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.02&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div style="text-align: justify; text-indent: 500.1pt;"&gt;&lt;br /&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We computed net income (loss) per share independently for each of the quarters presented. Therefore, the sum of the quarterly net income (loss) per share will not necessarily equal the total for the year.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;As discussed in Note 1, &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Organization and Significant Accounting Policies, &lt;/font&gt;we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income (loss) per share calculation for each of the quarters in 2018 and for the third and fourth quarters of 2017 considered our net income for Ionis on a stand-alone basis plus our share of Akcea&amp;#8217;s net loss for the period. To calculate the portion of Akcea&amp;#8217;s net loss attributable to our ownership, we multiplied Akcea&amp;#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our&amp;#160;total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our basic net income (loss) per share for each quarter in 2018 was calculated as follows (in thousands, except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended March 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Income (Loss)&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; Portion of&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;45,448&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.44&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(19,997&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; 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background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,785&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net loss available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; 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width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.01&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended June 30, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(37,932&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;128,712&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net loss per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.29&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended September 30, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Income (Loss)&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; 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padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net loss available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;67,130&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.79&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(53,219&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(53,219&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;372,913&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;319,694&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;137,699&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.32&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Prior to Akcea&amp;#8217;s IPO in July 2017, we owned Akcea series A convertible preferred stock, which included a six percent cumulative dividend. Upon completion of Akcea&amp;#8217;s IPO in July 2017, our preferred stock was converted into common stock on a 1:1 basis. The preferred stock dividend was not paid at the IPO because the IPO was not a liquidation event or a change in control. During the three months ended September 30, 2017, Akcea used a two-class method to compute its net income (loss) per share because it had both common and preferred shares outstanding during the periods. The two-class method required Akcea to calculate its net income (loss) per share&amp;#160;for each class of stock by dividing total distributable losses applicable to preferred and common stock, including the&amp;#160;six percent&amp;#160;cumulative dividend contractually due to series A convertible preferred shareholders, by the weighted-average of preferred and common shares outstanding during the requisite period. Since Akcea used the two-class method, accounting rules required us to include our portion of Akcea&amp;#8217;s net income (loss) per share for both Akcea&amp;#8217;s common and preferred shares that we owned in our calculation of basic and diluted net income (loss) per share for the three months ended September 30, 2017.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our basic net income (loss) per share for the three months ended &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;September 30, 2017&lt;/font&gt; was calculated as follows (in thousands, except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended September 30, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Loss&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Portion of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; 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vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;36,556&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.01&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(57&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,120&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; 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text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10,144&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net loss available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,976&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,370&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net loss per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.02&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: justify; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our basic net income (loss) per share for the three months ended &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 30, 2017&lt;/font&gt; was calculated as follows (in thousands, except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Loss&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Portion of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;45,448&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.30&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(13,634&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(13,634&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10,510&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net loss available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3,124&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,818&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net loss per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.03&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For the three months ended December 31, 2018, we had net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods. Diluted common equivalent shares for the three months ended December 31, 2018 consisted of the following (in thousands except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Income&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Numerator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Denominator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per-Share&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;319,694&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;137,699&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.32&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effect of dilutive securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon exercise of stock options&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,254&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon restricted stock award issuance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;636&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our ESPP&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our 1 percent convertible notes&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10,745&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10,260&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income available to Ionis common stockholders, plus assumed conversions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;330,439&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;149,856&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.21&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For the three months ended March 31, 2017, we owned 100 percent of Akcea. As a result, we did not have to adjust our earnings per share calculation. For the three months ended March 31, 2017, we had net income. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods. Diluted common equivalent shares for the three months ended March 31, 2017 consisted of the following (in thousands except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Three Months Ended March 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Income&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Numerator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Denominator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per-Share&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,964&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;122,861&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effect of dilutive securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon exercise of stock options&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,674&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon restricted stock award issuance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;377&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our ESPP&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;60&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,964&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,972&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;For the three months ended March 31, 2017, the calculation excluded the 1 percent and 2&amp;#190; percent notes because the effect on diluted earnings per share was anti-dilutive.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfQuarterlyFinancialInformationTableTextBlock>
  <!--Schedule of Effective Income Tax Rate Reconciliation [Table Text Block]-->
  <us-gaap:ScheduleOfEffectiveIncomeTaxRateReconciliationTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The reconciliation between our effective tax rate on loss from continuing operations and the statutory U.S. tax rate is as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="22" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Pre-tax loss&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(76,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(16,763&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(57,466&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 28%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Statutory rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(15,993&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,867&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Volatility&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;47.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;59.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;86.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expected life&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6 months&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6 months&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6 months&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfShareBasedPaymentAwardEmployeeStockPurchasePlanValuationAssumptionsTableTextBlock>
  <!--Schedule of Share-based Payment Award, Stock Options, Valuation Assumptions [Table Text Block]-Akcea Therapeutics, Inc. [Member]-->
  <us-gaap:ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock contextRef="c20180101to20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In addition to our stock plans, Akcea has its own stock plan under which it grants options and RSUs and under which it derives its stock-based compensation expense. The following are the weighted-average Black-Scholes assumptions Akcea used under its plan for the years ended December 31, 2018, 2017 and 2016:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Employee Stock Options:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Risk-free interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dividend yield&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Volatility&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;77.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;79.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;71.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expected life&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.08 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.06 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.08 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Board of Director Stock Options:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Risk-free interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dividend yield&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Volatility&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;78.2&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;79.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;79.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expected life&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.42 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.25 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.08 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock>
  <!--Schedule of Share-based Payment Award, Stock Options, Valuation Assumptions [Table Text Block]-->
  <us-gaap:ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the years ended December 31, 2018, 2017 and 2016, 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="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Employee Stock Options:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Risk-free interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dividend yield&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Volatility&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;63.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;65.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;58.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expected life&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4.6 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4.5 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4.5 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Board of Director Stock Options:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Risk-free interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.2&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dividend yield&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Volatility&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;61.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;61.2&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;53.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expected life&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.6 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.6 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.5 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock>
  <!--Schedule of Share-based Compensation, Restricted Stock and Restricted Stock Units Activity [Table Text Block]-->
  <us-gaap:ScheduleOfSharebasedCompensationRestrictedStockAndRestrictedStockUnitsActivityTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the RSU activity for the year ended December 31, 2018 (in thousands, except per share data):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Number of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted Average&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Grant Date Fair&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Value Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Non-vested at December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;863&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;49.55&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Granted&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;789&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;51.06&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Vested&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(324&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;50.21&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cancelled/forfeited&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(82&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;51.59&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Non-vested at December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,246&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;50.20&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfSharebasedCompensationRestrictedStockAndRestrictedStockUnitsActivityTableTextBlock>
  <!--Schedule of Earnings Per Share, Basic and Diluted [Table Text Block]-->
  <us-gaap:ScheduleOfEarningsPerShareBasicAndDilutedTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our diluted net income per share for 2018 as follows &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(in thousands except per share amounts):&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Income&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Numerator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Denominator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per-Share&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;276,868&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;132,320&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.09&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effect of dilutive securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon exercise of stock options&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,216&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon restricted stock award issuance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;514&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable related to our ESPP&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income available to Ionis common stockholders, plus assumed conversions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;276,868&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;134,056&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We calculated our diluted net income per share for 2017 as follows &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(in thousands except per share amounts):&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Income&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Numerator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Denominator)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per-Share&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Amount&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,792&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Effect of dilutive securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -8.9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon exercise of stock options&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,619&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 0.1pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Shares issuable upon restricted stock award issuance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;459&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; 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padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income available to Ionis common stockholders, plus assumed conversions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,792&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;126,098&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfEarningsPerShareBasicAndDilutedTableTextBlock>
  <!--Schedule of Temporary Impairment Losses, Investments [Table Text Block]-->
  <us-gaap:ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Investments we consider to be temporarily impaired at December 31, 2018 are as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Less than 12 Months of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Temporary Impairment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;More than 12 Months of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Temporary Impairment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Total Temporary&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Impairment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Number of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Investments&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; 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padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Unrealized&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Losses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Estimated&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 16%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total temporarily impaired securities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; 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vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,909&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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  <!--Share-based Compensation, Stock Options, Activity [Table Text Block]-->
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font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Number&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;of Shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Exercise&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Price Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Remaining&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Contractual Term&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Years)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Aggregate&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Intrinsic&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Value&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;17.78&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cancelled/forfeited/expired&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(540&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;52.47&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Outstanding at December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11,311&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;47.85&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4.41&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;93,663&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Exercisable at December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,071&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;46.83&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3.22&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;63,756&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfShareBasedCompensationStockOptionsActivityTableTextBlock>
  <!--Schedule of Income before Income Tax, Domestic and Foreign [Table Text Block]-->
  <us-gaap:ScheduleOfIncomeBeforeIncomeTaxDomesticAndForeignTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Loss before income tax (benefit) expense is comprised of (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;United States&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(69,576&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,289&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(57,466&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Foreign&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(6,580&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(11,474&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Loss before income tax (benefit) expense&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(76,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(16,763&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(57,466&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfIncomeBeforeIncomeTaxDomesticAndForeignTableTextBlock>
  <!--Schedule of Unrecognized Tax Benefits Roll Forward [Table Text Block]-->
  <us-gaap:ScheduleOfUnrecognizedTaxBenefitsRollForwardTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes our gross unrecognized tax benefits (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Beginning balance of unrecognized tax benefits&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;78,014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66,999&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;51,257&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Settlement of prior period tax positions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4,033&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Decrease for prior period tax positions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,814&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Increase for prior period tax positions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,520&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7,928&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Increase for current period tax positions&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3,101&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;9,495&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11,847&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ending balance of unrecognized tax benefits&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;68,301&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;78,014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66,999&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfUnrecognizedTaxBenefitsRollForwardTableTextBlock>
  <!--Schedule of Future Minimum Lease Payments for Capital Leases [Table Text Block]-->
  <us-gaap:ScheduleOfFutureMinimumLeasePaymentsForCapitalLeasesTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Annual future minimum payments under our operating leases as of December 31, 2018 are as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Operating&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Leases&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2019&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3,129&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2020&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3,008&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2021&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,725&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2022&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,539&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2023&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,505&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Thereafter&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11,862&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total minimum payments&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;25,768&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfFutureMinimumLeasePaymentsForCapitalLeasesTableTextBlock>
  <!--Schedule of Accumulated Other Comprehensive Income (Loss) [Table Text Block]-->
  <us-gaap:ScheduleOfAccumulatedOtherComprehensiveIncomeLossTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated other comprehensive loss is primarily comprised of unrealized gains and losses on investments, net of taxes and adjustments we made to reclassify realized gains and losses on investments from other accumulated comprehensive loss to our Consolidated Statement of Operations. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2018, 2017 and 2016 (in thousands):&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Beginning balance accumulated other comprehensive loss&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(31,759&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(30,358&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(13,565&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Unrealized losses on securities, net of tax (1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(280&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(960&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(17,219&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(67&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(21&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net other comprehensive loss for the period&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(257&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,401&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(31,759&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(30,358&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="display: inline-block; text-indent: 0px; font-size: 1px; width: 522pt;"&gt;&amp;#160;&lt;/font&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;A tax benefit of $0.3 million was included in other comprehensive loss for the year ended December 31, 2018. There was no tax benefit or expense for other comprehensive loss for the years ended December 31, 2017 or 2016.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfAccumulatedOtherComprehensiveIncomeLossTableTextBlock>
  <!--Schedule of Accrued Liabilities [Table Text Block]-->
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vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Clinical expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;22,125&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;16,347&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -18pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In-licensing expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;12,298&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;33,790&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -18pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Other miscellaneous expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;13,938&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;16,481&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total accrued liabilities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;48,361&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;66,618&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfAccruedLiabilitiesTableTextBlock>
  <!--Schedule of Components of Income Tax Expense (Benefit) [Table Text Block]-->
  <us-gaap:ScheduleOfComponentsOfIncomeTaxExpenseBenefitTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our income tax (benefit) expense was as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Current:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Federal&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;438&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(7,460&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,067&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;State&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,442&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,246&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,867&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Foreign&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;374&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;234&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total current income tax (benefit) expense&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(630&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,980&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,934&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; 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width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; 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text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total deferred income tax (benefit) expense&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(290,511&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total income tax (benefit) expense&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(291,141&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,980&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,934&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfComponentsOfIncomeTaxExpenseBenefitTableTextBlock>
  <!--Schedule of Deferred Tax Assets and Liabilities [Table Text Block]-->
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font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred Tax Assets:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net operating loss carryovers&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;89,717&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;153,575&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D credits&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;313,652&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;240,290&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;27,381&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;54,302&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Stock-based compensation&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;61,027&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;40,090&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Intangible and capital assets&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;49,007&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;672&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Other&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,275&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;12,164&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total deferred tax assets&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;549,059&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;501,093&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred Tax Liabilities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Convertible debt&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(24,018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(32,391&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net deferred tax asset&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;525,041&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;468,702&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Valuation allowance&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(234,245&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(468,702&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total net deferred tax assets and liabilities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;290,796&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfDeferredTaxAssetsAndLiabilitiesTableTextBlock>
  <!--Schedule of Long-term Debt Instruments [Table Text Block]-->
  <us-gaap:ScheduleOfDebtInstrumentsTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The carrying value of our long-term obligations was as follows (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1 percent convertible senior notes&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;568,215&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;533,111&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Long-term mortgage debt&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;59,842&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;59,771&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Principal balance of fixed rate note with Morgan Stanley (1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;12,500&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;12,500&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Leases and other obligations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,163&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,095&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;646,720&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;607,477&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Less: current portion&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(13,749&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,621&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total Long-Term Obligations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;632,971&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;605,856&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Our $12.5 million fixed rate note with Morgan Stanley is included in our current portion of long-term obligations on our consolidated balance sheet at December 31, 2018.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfDebtInstrumentsTextBlock>
  <!--Schedule of Earnings Per Share, Basic, by Common Class, Including Two Class Method [Table Text Block]-->
  <us-gaap:ScheduleOfEarningsPerShareBasicByCommonClassTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Our basic net income per share for &lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2018&lt;/font&gt;, was calculated as follows (in thousands, except per share amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Income (Loss)&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Portion of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;59,812&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2.74&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(163,938&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(163,938&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;440,806&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;276,868&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;132,320&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.09&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;We calculated our basic net income per share for 2017 as follows (in thousands, except per share amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Shares&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Owned in Akcea&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Net Loss&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis&lt;/font&gt;&amp;#8217;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Portion of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;s Net Loss&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Common shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;20,669&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3.08&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(63,638&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Preferred shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;15,748&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1.80&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(28,346&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea&amp;#8217;s net loss attributable to our ownership&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(91,984&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ionis&amp;#8217; stand-alone net income&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;110,776&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income available to Ionis common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,792&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Weighted average shares outstanding&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;124,016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Basic net income per share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfEarningsPerShareBasicByCommonClassTextBlock>
  <!--Schedule of Employee Service Share-based Compensation, Allocation of Recognized Period Costs [Table Text Block]-->
  <us-gaap:ScheduleOfEmployeeServiceShareBasedCompensationAllocationOfRecognizedPeriodCostsTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes stock-based compensation expense for the years ended December 31, 2018, 2017 and 2016 (in thousands), which was allocated as follows and includes $44.3 million, $17.5 million and $10.1 million of stock-based compensation expense for Akcea employees in 2018, 2017 and 2016, respectively:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cost of products sold&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;160&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Research, development and patent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;76,557&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;64,521&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;55,099&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Selling, general and administrative&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;54,595&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21,454&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;17,009&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;131,312&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;85,975&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;72,108&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfEmployeeServiceShareBasedCompensationAllocationOfRecognizedPeriodCostsTextBlock>
  <!--Schedule of New Accounting Pronouncements and Changes in Accounting Principles [Table Text Block]-->
  <us-gaap:ScheduleOfNewAccountingPronouncementsAndChangesInAccountingPrinciplesTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following tables summarize the adjustments we were required to make to amounts we originally reported in 2017 and 2016 to adopt Topic 606 (in thousands, except per share amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Consolidated Balance Sheet&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;At December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Current portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;106,465&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,871&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;125,336&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Long-term portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;72,708&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;35,318&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;108,026&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Accumulated deficit&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,187,398&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(53,636&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,241,034&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&amp;#160;&amp;#160;Noncontrolling interest in Akcea Therapeutics, Inc.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;87,847&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3,580&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,267&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total stockholders&amp;#8217; equity&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;418,719&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(53,439&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;365,280&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Consolidated Statements of Operations&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Revenue:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Commercial revenue:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;SPINRAZA royalties&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;112,540&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;-&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;112,540&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;9,519&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7,474&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;122,059&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120,014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Research and development revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;385,607&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8,558&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;394,165&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;507,666&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;514,179&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;24,534&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;31,047&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; 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width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(10,783&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(5,970&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,316&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;346&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income per share, basic and diluted&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.08&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.07&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.15&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;883&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;19,839&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21,884&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: 17.75pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;20,722&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,045&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;22,767&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Research and development revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;325,898&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;24,111&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;350,009&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;346,620&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;372,776&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income (loss) from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(46,316&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(20,160&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(86,556&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(60,400&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(86,556&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(60,400&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss) per share, basic and diluted&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.72&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.22&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(0.50&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;"&gt;Consolidated Statements of Cash Flows&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(17,296&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(10,783&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27.15pt; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;36,695&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(6,513&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;30,182&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at beginning of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at end of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;129,630&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;129,630&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31, 2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net income (loss)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(86,556&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(60,400&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27.15pt; margin-left: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(59,150&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(26,156&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(85,306&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at beginning of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;128,797&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;128,797&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cash and cash equivalents at end of year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;84,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the adjustments we were required to make to our deferred revenue amounts to adopt Topic 606 (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;At December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Previously&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Reported under&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 605&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Topic 606&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;As Revised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Current portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;106,465&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;18,871&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;125,336&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Long-term portion of deferred contract revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;72,708&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;35,318&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;108,026&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total deferred revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;179,173&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;54,189&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;233,362&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfNewAccountingPronouncementsAndChangesInAccountingPrinciplesTextBlock>
  <!--Segment Information-->
  <us-gaap:ScheduleOfSegmentReportingInformationBySegmentTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following tables show our segment revenue and income (loss) from operations for &lt;/font&gt;2018, 2017 and 2016&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; (in thousands), respectively.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis Core&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea Therapeutics&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" nowrap="nowrap" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Elimination of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Intercompany Activity&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Revenue:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&lt;div style="text-align: left; margin-left: 7.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Commercial revenue:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;SPINRAZA royalties&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;237,930&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;237,930&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;TEGSEDI product sales, net&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,237&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,237&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,755&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;12,000&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;14,755&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 43.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;240,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;14,237&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;254,922&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 7.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;401,259&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;50,630&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(107,137&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;344,752&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total segment revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;641,944&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;64,867&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(107,137&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;599,674&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total operating expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;380,212&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;295,683&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(14,849&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;661,046&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income (loss) from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; 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width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; 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width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7,474&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 43.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120,014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 7.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;405,171&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; 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font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;394,165&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total segment revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;525,185&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;43,401&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(54,407&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;514,179&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total operating expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;373,788&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;163,871&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(54,527&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;483,132&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income (loss) from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;151,397&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(120,470&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;31,047&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016 (as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis Core&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea Therapeutics&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" nowrap="nowrap" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Elimination of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Intercompany Activity&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Revenue:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&lt;div style="text-align: left; margin-left: 7.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Commercial revenue:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;SPINRAZA royalties&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;883&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;883&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21,884&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21,884&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 43.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;22,767&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;22,767&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 7.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;362,657&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,648&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;350,009&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total segment revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;385,424&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,648&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;372,776&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total operating expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;322,192&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;83,512&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,768&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;392,936&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income (loss) from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;63,232&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(83,512&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(20,160&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following table shows our total assets by segment at December 31, 2018 and 2017 (in thousands), respectively.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Total Assets&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis Core&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea Therapeutics&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" nowrap="nowrap" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Elimination of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Intercompany Activity&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,975,491&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;365,261&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(672,968&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,667,784&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 31, 2017 (as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,342,578&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;268,804&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(288,608&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,322,774&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:ScheduleOfSegmentReportingInformationBySegmentTextBlock>
  <!--Schedules of Concentration of Risk, by Risk Factor [Table Text Block]-Collaborative Arrangements and Licensing Agreements, AstraZeneca [Member]-->
  <us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;41.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;20&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
  <!--Schedules of Concentration of Risk, by Risk Factor [Table Text Block]-Collaborative Arrangements and Licensing Agreements, Biogen [Member]-->
  <us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementsAndLicensingAgreementsBiogenMember">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;SPINRAZA royalties (commercial revenue)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;237.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;112.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;137.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;150.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;248.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total revenue from our relationship with Biogen&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;375.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;263.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;249.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;63&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;51&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;67&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
  <!--Schedules of Concentration of Risk, by Risk Factor [Table Text Block]-Collaborative Arrangements and Licensing Agreements, Bayer [Member]-->
  <us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementsAndLicensingAgreementsBayerMember">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;67.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;13&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
  <!--Schedules of Concentration of Risk, by Risk Factor [Table Text Block]-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-->
  <us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;14.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;17.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
  <!--Schedules of Concentration of Risk, by Risk Factor [Table Text Block]-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Janssen (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;36.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;24.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
  <!--Schedules of Concentration of Risk, by Risk Factor [Table Text Block]-Collaborative Arrangements and Licensing Agreements, Roche [Member]-->
  <us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementsAndLicensingAgreementsRocheMember">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;55.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;10.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
  <!--Schedules of Concentration of Risk, by Risk Factor [Table Text Block]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;During the years ended December 31, 2018 and 2017, we earned the following revenue from our relationship with Novartis (in millions, except percentage amounts):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Years Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;50.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;43.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Percentage of total revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:SchedulesOfConcentrationOfRiskByRiskFactorTextBlock>
  <!--Segment Reporting, Policy [Policy Text Block]-->
  <us-gaap:SegmentReportingPolicyPolicyTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Segment Information&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have two operating segments, our Ionis Core segment and Akcea Therapeutics, our majority-owned affiliate. Akcea is &lt;/font&gt;a biopharmaceutical company focused on developing and commercializing medicines to treat patients with rare and serious diseases&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;. We provide segment financial information and results for our Ionis Core segment and our Akcea Therapeutics segment based on the segregation of revenues and expenses that our chief decision maker reviews to assess operating performance and to make operating decisions. We allocate a portion of Ionis&amp;#8217; development, R&amp;amp;D support and general and administrative expenses to Akcea for work Ionis performs on behalf of Akcea.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:SegmentReportingPolicyPolicyTextBlock>
  <!--Segment Information and Concentration of Business Risk-->
  <us-gaap:SegmentReportingDisclosureTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;7. Segment Information and Concentration of Business Risk&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We have two reportable segments Ionis Core and Akcea Therapeutics. &lt;/font&gt;At December 31, 2018, we owned approximately 75 percent of Akcea.&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; Segment income (loss) from operations includes revenue less operating expenses attributable to each segment.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In our Ionis Core segment we are exploiting our antisense technology to generate a broad pipeline of first-in-class and/or best-in-class medicines for us and our partners. Our Ionis Core segment generates revenue from a multifaceted partnering strategy.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Akcea is &lt;/font&gt;a biopharmaceutical company focused on developing and commercializing medicines to treat patients with rare and serious diseases&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following tables show our segment revenue and income (loss) from operations for &lt;/font&gt;2018, 2017 and 2016&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; (in thousands), respectively.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis Core&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea Therapeutics&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" nowrap="nowrap" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Elimination of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; 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vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top;"&gt;&lt;div style="text-align: left; 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vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;SPINRAZA royalties&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;237,930&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;237,930&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;TEGSEDI product sales, net&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,237&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,237&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,755&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;12,000&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;14,755&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 43.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;240,685&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;14,237&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 7.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;401,259&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(107,137&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;599,674&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income (loss) from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; 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font-family: 'Times New Roman', Times, serif;"&gt;(92,288&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(61,372&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017 (as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;SPINRAZA royalties&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;112,540&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;112,540&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7,474&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;7,474&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 43.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120,014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120,014&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 7.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;R&amp;amp;D revenue under collaborative agreements&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;405,171&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;43,401&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(54,407&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;394,165&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total segment revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;525,185&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;43,401&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(54,407&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;514,179&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total operating expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;373,788&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;163,871&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(54,527&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;31,047&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016 (as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Licensing and other royalty revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21,884&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21,884&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 43.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total commercial revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;22,767&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;362,657&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;350,009&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; margin-left: 25.2pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total segment revenue&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;385,424&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,648&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;372,776&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total operating expenses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;322,192&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;83,512&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(12,768&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;392,936&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Income (loss) from operations&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;63,232&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(83,512&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;120&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(20,160&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&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="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The following table shows our total assets by segment at December 31, 2018 and 2017 (in thousands), respectively.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Total Assets&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Ionis Core&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Akcea Therapeutics&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" nowrap="nowrap" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Elimination of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Intercompany Activity&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;365,261&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(672,968&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2,667,784&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: top; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -10pt; margin-left: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;December 31, 2017 (as revised)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; 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vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;268,804&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(288,608&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,322,774&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Contracts receivables at December 31, 2018 and December&amp;#160;31, 2017 were comprised of approximately 99 percent and 84&amp;#160; percent for each year from four and two significant partners, respectively.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:SegmentReportingDisclosureTextBlock>
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  <us-gaap:StockholdersEquityPolicyTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Accumulated Other Comprehensive Loss&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;Accumulated other comprehensive loss is primarily comprised of unrealized gains and losses on investments, net of taxes and adjustments we made to reclassify realized gains and losses on investments from other accumulated comprehensive loss to our Consolidated Statement of Operations. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2018, 2017 and 2016 (in thousands):&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Beginning balance accumulated other comprehensive loss&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(31,759&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(30,358&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(13,565&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Unrealized losses on securities, net of tax (1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(280&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(960&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(17,219&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Amounts reclassified from accumulated other comprehensive loss&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(374&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;447&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Currency translation adjustment&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;23&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(67&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(21&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Net other comprehensive loss for the period&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(257&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,401&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(16,793&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Ending balance accumulated other comprehensive loss&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(32,016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(31,759&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; 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  <us-gaap:StockholdersEquityNoteDisclosureTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;4. Stockholders&lt;/font&gt;&amp;#8217;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; Equity&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Preferred Stock&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We are authorized to issue up to 15,000,000 shares of &amp;#8220;blank check&amp;#8221; Preferred Stock. As of December 31, 2018, there were no shares of Preferred Stock outstanding. We have designated Series&amp;#160;C Junior Participating Preferred Stock but have no issued or outstanding shares as of December 31, 2018.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Common Stock&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;At December 31, 2018 and 2017, we had 300,000,000 shares of common stock authorized, of which 137,928,828 and 124,976,373 were issued and outstanding, respectively. As of December 31, 2018, total common shares reserved for future issuance were 14,839,373.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;During the years ended December 31, 2018, 2017 and 2016, we issued 1,451,000, 1,709,000 and 1,285,000 shares of common stock, respectively, for stock option exercises, vesting of restricted stock units, and ESPP purchases. We received net proceeds from these transactions of $27.9 million, $22.9 million and $13.7 million in 2018, 2017 and 2016, respectively.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Stock Plans&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;1989 Stock Option Plan&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In June 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as amended, provides for the issuance of non-qualified and incentive stock options for the purchase of up to 20,000,000 shares of common stock to our employees, directors, and consultants. The plan expires in January 2024. The 1989 Plan does not allow us to grant stock bonuses or restricted stock awards and prohibits us from repricing any options outstanding under the plan unless our stockholders approve the repricing. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. At December 31, 2018, a total of 848,753 options were outstanding, of which options to purchase 831,656 shares were exercisable, and 42,925 shares were available for future grant under the 1989 Plan.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;2011 Equity Incentive Plan&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In March 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to our employees, directors, and consultants.&amp;#160;In June 2015 and in May 2017, after receiving approval from our stockholders, we amended our 2011 Equity Incentive Plan to increase the total number of shares reserved for issuance. We increased the shares available under our 2011 Equity Incentive Plan from 5,500,000 to 11,000,000 in June 2015 and from 11,000,000 to 16,000,000 in May 2017. The plan expires in June&amp;#160;2021. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only options and restricted stock unit awards to our employees, directors and consultants. Under the 2011 Plan, stock options cannot vest in a period of less than two years and restricted stock unit awards cannot vest in a period of less than three years. We have granted restricted stock unit awards to our employees under the 2011 Plan which vest annually over a four-year period. At December 31, 2018, a total of 9,705,441 options were outstanding, of which 4,801,904 were exercisable, 1,183,154 restricted stock unit awards were outstanding, and 3,340,351 shares were available for future grant under the 2011 Plan.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a change in control. In the absence of such provisions, no such acceleration will occur. The stock options and restricted stock unit awards we issue to our chief executive officer and issued to B. Lynne Parshall in her former role as chief operating officer will accelerate upon a change of control, as defined in the 2011 Plan. In addition, we implemented a change of control and severance benefit plan that provides for change of control and severance benefits to our executive officers, including our chief executive officer and chief financial officer. If we terminate one of our executive officers or if an executive officer resigns for good reason during the period that begins three months before and ends twelve months following a change in control of the company, the impacted executive officers&amp;#8217; stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the termination date.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Corporate Transactions and Change in Control under 2011 Plan&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more of the following actions with respect to outstanding stock awards under the 2011&amp;#160;Plan:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;arrange for assumption, continuation, or substitution of a stock award by a surviving or acquiring entity (or its parent company);&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;arrange for the assignment of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award to the surviving or acquiring corporation (or its parent company);&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;accelerate the vesting and exercisability of a stock award followed by the termination of the stock award;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;arrange for the lapse of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;cancel or arrange for the cancellation of a stock award, to the extent not vested or not exercised prior to the effective date of the corporate transaction, in exchange for cash consideration, if any, as the Board, in its sole discretion, may consider appropriate; and&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 36pt;"&gt;&lt;/td&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#9679;&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;arrange for the surrender of a stock award in exchange for a payment equal to the excess of (a)&amp;#160;the value of the property the holder of the stock award would have received upon the exercise of the stock award, over (b)&amp;#160;any exercise price payable by such holder in connection with such exercise.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#160;&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;2002 Non-Employee Directors&amp;#8217; Stock Option Plan&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In September 2001, our Board of Directors adopted, and the stockholders subsequently approved, an amendment and restatement of the 1992 Non-Employee Directors&amp;#8217; Stock Option Plan, which provides for the issuance of non-qualified stock options and restricted stock units to our non-employee directors. The name of the resulting plan is the 2002 Non-Employee Directors&amp;#8217; Stock Option Plan, or the 2002 Plan. In June 2015, after receiving approval from our stockholders, we amended our 2002 Non-Employee Directors Stock Option Plan to increase the total number of shares reserved for issuance. We increased the shares available under our 2002 Non-Employee Directors Stock Option Plan from 1,200,000 to 2,000,000. Options under this plan expire ten years from the date of grant. Options granted become exercisable in four equal annual installments beginning one year after the date of grant. At December 31, 2018, a total of 757,750 options were outstanding, of which 437,750 were exercisable, 63,099 restricted stock unit awards were outstanding, and 420,762 shares were available for future grant under the 2002 Plan.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Employee Stock Purchase Plan&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;In June 2009, our Board of Directors adopted, and the stockholders subsequently approved, the amendment and restatement of the ESPP and we reserved an additional 150,000 shares of common stock for issuance thereunder. In each of the subsequent years, we reserved an additional 150,000 shares of common stock for the ESPP resulting in a total of 3,674,596 shares authorized under the plan as of December 31, 2018. The ESPP permits full-time employees to purchase common stock through payroll deductions (which cannot exceed 10 percent of each employee&amp;#8217;s compensation) at the lower of 85 percent of fair market value at the beginning of the purchase period or the end of each six-month purchase period. Under the amended and restated ESPP, employees must hold the stock they purchase for a minimum of six months from the date of purchase. During 2018, employees purchased and we issued to employees 43,416 shares under the ESPP at a weighted average price of $39.03 per share. At December 31, 2018, there were 774,816 shares available for purchase under the ESPP.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Stock Option Activity&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2018 (in thousands, except per share and contractual life data):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Number&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;of Shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average Exercise&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Price Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Average&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Remaining&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Contractual Term&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;(Years)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Aggregate&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Intrinsic&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Value&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Outstanding at December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;9,397&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;44.52&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Granted&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3,518&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;48.40&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Exercised&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,064&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;17.78&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cancelled/forfeited/expired&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(540&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;52.47&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Outstanding at December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;11,311&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;47.85&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4.41&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;93,663&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Exercisable at December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6,071&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;46.83&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3.22&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;63,756&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The weighted-average estimated fair values of options granted were $25.49, $25.42 and $26.72 for the years ended December 31, 2018, 2017 and 2016, respectively. The total intrinsic value of options exercised during the years ended December 31, 2018, 2017 and 2016 were $34.8 million, $49.5 million and $28.0 million, respectively, which we determined as of the date of exercise. The amount of cash received from the exercise of stock options was $18.9 million, $21.2 million and $12.6 million for the years ended December 31, 2018, 2017 and 2016, respectively. For the year ended December 31, 2018, the weighted-average fair value of options exercised was $50.50. As of December 31, 2018, total unrecognized compensation cost related to non-vested stock-based compensation plans was $118.3 million. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures. We expect to recognize this cost over a weighted average period of 1.2 years.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Restricted Stock Unit Activity&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes the RSU activity for the year ended December 31, 2018 (in thousands, except per share data):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Number of&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Shares&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Weighted Average&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Grant Date Fair&lt;/font&gt;&lt;/div&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Value Per Share&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Non-vested at December 31, 2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;863&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;49.55&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Granted&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;789&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;51.06&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Vested&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(324&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;50.21&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 18pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cancelled/forfeited&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(82&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;51.59&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Non-vested at December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,246&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;50.20&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the years ended December 31, 2018, 2017 and 2016, the weighted-average grant date fair value of RSUs granted was $51.06, $48.88 and $41.79 per RSU, respectively. As of December 31, 2018, total unrecognized compensation cost related to RSUs was $27.9 million. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures. We expect to recognize this cost over a weighted average period of 1.4 years.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Stock-based Compensation Expense and Valuation Information&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following table summarizes stock-based compensation expense for the years ended December 31, 2018, 2017 and 2016 (in thousands), which was allocated as follows and includes $44.3 million, $17.5 million and $10.1 million of stock-based compensation expense for Akcea employees in 2018, 2017 and 2016, respectively:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Year Ended December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Cost of products sold&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;160&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Research, development and patent&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;76,557&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;64,521&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;55,099&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Selling, general and administrative&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;54,595&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;21,454&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;17,009&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;131,312&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;85,975&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;72,108&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: -18pt; margin-left: 54pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;Determining Fair Value&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Valuation.&lt;/font&gt; We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, and stock purchase rights under the ESPP at the grant date, based on the estimated fair value of the award and we recognize the expense over the employee&amp;#8217;s requisite service period. We value RSUs based on the market price of our common stock on the date of grant.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP. The expected term of stock options granted represents the period of time that we expect them to be outstanding. We estimate the expected term of options granted based on actual and projected exercise patterns. We recognize compensation expense for stock options granted, RSUs, 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;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;For the years ended December 31, 2018, 2017 and 2016, 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="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Employee Stock Options:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Risk-free interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dividend yield&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Volatility&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;63.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;65.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;58.7&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expected life&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4.6 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4.5 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;4.5 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Board of Director Stock Options:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Risk-free interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.2&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dividend yield&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Volatility&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;61.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;61.2&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;53.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expected life&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.6 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.6 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.5 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;"&gt;ESPP:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Risk-free interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dividend yield&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Volatility&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;47.3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;59.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;86.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expected life&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6 months&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6 months&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6 months&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Risk-Free Interest Rate.&lt;/font&gt; We base the risk-free interest rate assumption on observed interest rates appropriate for the term of our stock option plans or ESPP.&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Dividend Yield.&lt;/font&gt; We base the dividend yield assumption on our history and expectation of dividend payouts. We have not paid dividends in the past and do not expect to in the future.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Volatility.&lt;/font&gt; We use an average of the historical stock price volatility of our stock for the Black-Scholes model. We computed the historical stock volatility based on the expected term of the awards.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Expected Life. &lt;/font&gt;The expected term of stock options we have granted represents the period of time that we expect them to be outstanding. We estimated the expected term of options we have granted based on actual and projected exercise patterns.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Forfeitures.&lt;/font&gt; We reduce stock-based compensation expense for estimated forfeitures. We estimate forfeitures at the time of grant and revise, if necessary, in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on historical experience. Our historical forfeiture estimates have not been materially different from our actual forfeitures.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;In addition to our stock plans, Akcea has its own stock plan under which it grants options and RSUs and under which it derives its stock-based compensation expense. The following are the weighted-average Black-Scholes assumptions Akcea used under its plan for the years ended December 31, 2018, 2017 and 2016:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Employee Stock Options:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Risk-free interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dividend yield&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Volatility&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;77.1&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;79.5&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;71.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expected life&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.08 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.06 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.08 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Board of Director Stock Options:&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31,&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt; 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;2016&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Risk-free interest rate&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1.9&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Dividend yield&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;0.0&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Volatility&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;78.2&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;79.4&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;79.6&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;%&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Expected life&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.42 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.25 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"&gt;&lt;div style="text-align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;6.08 years&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;"&gt;&amp;#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; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following summarizes the Black-Scholes input methodology for Akcea options that differs from the methodology we use for Ionis options:&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Volatility.&lt;/font&gt; Since Akcea does not have sufficient history to estimate the volatility of its common stock, Akcea calculates its expected volatility based on a blend of its historical volatility and reported data from selected publicly traded peer companies for which historical information is available. Akcea plans to continue to use this blend to calculate its volatility until the historical volatility of its common stock is sufficient to measure expected volatility for future option grants.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;"&gt;Expected Life. &lt;/font&gt;Since Akcea does not have sufficient historical information, it uses the simplified method for estimating its expected term. Under the simplified method Akcea calculates its expected term as the average time-to-vesting and the contractual life of the options. As Akcea gains additional historical information, it will transition to calculating its expected term based on its exercise patterns.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:StockholdersEquityNoteDisclosureTextBlock>
  <!--Stockholders' Equity Attributable to Parent-->
  <us-gaap:StockholdersEquity contextRef="c20171231" unitRef="U001" decimals="-3">281013000</us-gaap:StockholdersEquity>
  <!--Stockholders' Equity Attributable to Parent-->
  <us-gaap:StockholdersEquity contextRef="c20181231" unitRef="U001" decimals="-3">1048079000</us-gaap:StockholdersEquity>
  <!--Tax Credit Carryforward, Amount-Research Tax Credit Carryforward [Member]-Federal [Member]-->
  <us-gaap:TaxCreditCarryforwardAmount contextRef="c20181231_IncomeTaxAuthorityNameAxis_InternalRevenueServiceIRSMember_TaxCreditCarryforwardAxis_ResearchMember" unitRef="U001" decimals="-5">288900000</us-gaap:TaxCreditCarryforwardAmount>
  <!--Tax Credit Carryforward, Amount-California Franchise Tax Board [Member]-Research Tax Credit Carryforward [Member]-->
  <us-gaap:TaxCreditCarryforwardAmount contextRef="c20181231_IncomeTaxAuthorityNameAxis_CaliforniaFranchiseTaxBoardMember_TaxCreditCarryforwardAxis_ResearchMember" unitRef="U001" decimals="-5">68400000</us-gaap:TaxCreditCarryforwardAmount>
  <!--Unrealized Gain (Loss) on Investments [Table Text Block]-->
  <us-gaap:UnrealizedGainLossOnInvestmentsTableTextBlock contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;The following is a summary of our investments (in thousands):&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;December 31, 2018&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Cost &lt;/font&gt;(1)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Gains&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Losses&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Fair Value&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Available-for-sale securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Corporate debt securities (2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;956,879&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;13&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,858&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;955,034&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by U.S. government agencies&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;168,839&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;3&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(104&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; 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padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;16,980&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(287&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;16,693&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total securities with a maturity of more than one year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;439,387&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;388&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,706&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;438,069&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total available-for-sale securities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,873,317&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;419&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4,068&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,869,668&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Equity securities:&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total equity securities included in other current assets (3)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,212&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;137&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,349&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total available-for-sale and equity securities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,874,529&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; 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font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(4,068&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;1,871,017&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"&gt;&amp;#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" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Gross Unrealized&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="2" valign="bottom" style="vertical-align: bottom;"&gt;&lt;div style="text-align: center;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"&gt;Estimated&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Corporate debt securities (2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;500,599&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;2&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; 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font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;499,849&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by U.S. government agencies&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;83,926&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(212&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;83,714&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by the U.S. Treasury&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;29,428&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&amp;#8212;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(17&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;29,411&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Debt securities issued by states of the U.S. and political subdivisions of the states (2)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;64,810&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total securities with a maturity of more than one year&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;268,401&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;8&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1,969&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;266,440&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Total available-for-sale securities&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;911,594&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;14&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3,072&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;)&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;$&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;908,536&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"&gt;&amp;#160;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(1)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We hold our available-for-sale securities at amortized cost.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: left;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(2)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: left;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;Includes investments classified as cash equivalents on our consolidated balance sheet.&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify;"&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%;"&gt;&lt;tr&gt;&lt;td style="width: 18pt; vertical-align: top; align: right;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;(3)&lt;/font&gt;&lt;/td&gt;&lt;td style="width: auto; vertical-align: top; text-align: justify;"&gt;&lt;div&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;We recognize our equity securities at&lt;/font&gt; cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt; on our consolidated balance sheet.&lt;/font&gt;&lt;/font&gt;&lt;/div&gt;&lt;/td&gt;&lt;/tr&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:UnrealizedGainLossOnInvestmentsTableTextBlock>
  <!--Unrecognized tax benefits that could impact effective tax rate, if recognized-->
  <us-gaap:UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate contextRef="c20181231" unitRef="U001" decimals="-5">55500000</us-gaap:UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate>
  <!--Unrecognized Tax Benefits, Decrease Resulting from Settlements with Taxing Authorities-->
  <us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromSettlementsWithTaxingAuthorities contextRef="c20180101to20181231" unitRef="U001" decimals="-3">0</us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromSettlementsWithTaxingAuthorities>
  <!--Unrecognized Tax Benefits, Decrease Resulting from Settlements with Taxing Authorities-->
  <us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromSettlementsWithTaxingAuthorities contextRef="c20170101to20171231" unitRef="U001" decimals="-3">0</us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromSettlementsWithTaxingAuthorities>
  <!--Unrecognized Tax Benefits, Decrease Resulting from Settlements with Taxing Authorities-->
  <us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromSettlementsWithTaxingAuthorities contextRef="c20160101to20161231" unitRef="U001" decimals="-3">4033000</us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromSettlementsWithTaxingAuthorities>
  <!--Unrecognized Tax Benefits, Increase Resulting from Prior Period Tax Positions-->
  <us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions contextRef="c20170101to20171231" unitRef="U001" decimals="-3">1520000</us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions>
  <!--Unrecognized Tax Benefits, Increase Resulting from Prior Period Tax Positions-->
  <us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions contextRef="c20180101to20181231" unitRef="U001" decimals="-3">0</us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions>
  <!--Unrecognized Tax Benefits, Increase Resulting from Prior Period Tax Positions-->
  <us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions contextRef="c20160101to20161231" unitRef="U001" decimals="-3">7928000</us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions>
  <!--Unrecognized Tax Benefits, Decrease Resulting from Prior Period Tax Positions-->
  <us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions contextRef="c20160101to20161231" unitRef="U001" decimals="-3">0</us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions>
  <!--Unrecognized Tax Benefits, Decrease Resulting from Prior Period Tax Positions-->
  <us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions contextRef="c20180101to20181231" unitRef="U001" decimals="-3">12814000</us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions>
  <!--Unrecognized Tax Benefits, Decrease Resulting from Prior Period Tax Positions-->
  <us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions contextRef="c20170101to20171231" unitRef="U001" decimals="-3">0</us-gaap:UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions>
  <!--Unrecognized Tax Benefits, Increase Resulting from Current Period Tax Positions-->
  <us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions contextRef="c20180101to20181231" unitRef="U001" decimals="-3">3101000</us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions>
  <!--Unrecognized Tax Benefits, Increase Resulting from Current Period Tax Positions-->
  <us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions contextRef="c20160101to20161231" unitRef="U001" decimals="-3">11847000</us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions>
  <!--Unrecognized Tax Benefits, Increase Resulting from Current Period Tax Positions-->
  <us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions contextRef="c20170101to20171231" unitRef="U001" decimals="-3">9495000</us-gaap:UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions>
  <!--Unrecognized Tax Benefits-->
  <us-gaap:UnrecognizedTaxBenefits contextRef="c20151231" unitRef="U001" decimals="-3">51257000</us-gaap:UnrecognizedTaxBenefits>
  <!--Unrecognized Tax Benefits-->
  <us-gaap:UnrecognizedTaxBenefits contextRef="c20161231" unitRef="U001" decimals="-3">66999000</us-gaap:UnrecognizedTaxBenefits>
  <!--Unrecognized Tax Benefits-->
  <us-gaap:UnrecognizedTaxBenefits contextRef="c20171231" unitRef="U001" decimals="-3">78014000</us-gaap:UnrecognizedTaxBenefits>
  <!--Unrecognized Tax Benefits-->
  <us-gaap:UnrecognizedTaxBenefits contextRef="c20181231" unitRef="U001" decimals="-3">68301000</us-gaap:UnrecognizedTaxBenefits>
  <!--Unrecognized Tax Benefits, Income Tax Penalties and Interest Expense-->
  <us-gaap:UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense contextRef="c20180101to20181231" unitRef="U001" decimals="-3">0</us-gaap:UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense>
  <!--Use of Estimates, Policy [Policy Text Block]-->
  <us-gaap:UseOfEstimates contextRef="c20180101to20181231">&lt;div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"&gt;&lt;div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;"&gt;Use of Estimates&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;div style="text-align: justify; text-indent: 36pt;"&gt;&lt;font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"&gt;The preparation of consolidated financial statements in conformity with accounting principles generally accepted in the U.S. requires management to make estimates and assumptions that affect the amounts reported in the consolidated financial statements and accompanying notes. Actual results could differ from those estimates.&lt;/font&gt;&lt;/div&gt;&lt;div&gt;&lt;br /&gt;&lt;/div&gt;&lt;/div&gt;</us-gaap:UseOfEstimates>
  <!--SEC Schedule, 12-09, Valuation Allowances and Reserves, Period Increase (Decrease)-->
  <us-gaap:ValuationAllowancesAndReservesPeriodIncreaseDecrease contextRef="c20180101to20181231" unitRef="U001" decimals="-5">-234500000</us-gaap:ValuationAllowancesAndReservesPeriodIncreaseDecrease>
  <!--Shares used in computing basic net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic contextRef="c20180101to20181231" unitRef="U002" decimals="-3">132320000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
  <!--Shares used in computing basic net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic contextRef="c20170101to20171231" unitRef="U002" decimals="-3">124016000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
  <!--Shares used in computing basic net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic contextRef="c20160101to20161231" unitRef="U002" decimals="-3">120933000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
  <!--Shares used in computing basic net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic contextRef="c20170701to20170930" unitRef="U002" decimals="-3">124370000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
  <!--Shares used in computing basic net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic contextRef="c20181001to20181231" unitRef="U002" decimals="-3">137699000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
  <!--Shares used in computing basic net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic contextRef="c20180101to20180331" unitRef="U002" decimals="-3">125330000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
  <!--Shares used in computing basic net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic contextRef="c20180401to20180630" unitRef="U002" decimals="-3">128712000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
  <!--Shares used in computing basic net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic contextRef="c20170101to20170331" unitRef="U002" decimals="-3">122861000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
  <!--Shares used in computing basic net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic contextRef="c20171001to20171231" unitRef="U002" decimals="-3">124818000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
  <!--Shares used in computing basic net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfSharesOutstandingBasic contextRef="c20180701to20180930" unitRef="U002" decimals="-3">137346000</us-gaap:WeightedAverageNumberOfSharesOutstandingBasic>
  <!--Shares used in computing diluted net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding contextRef="c20180101to20181231" unitRef="U002" decimals="-3">134056000</us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding>
  <!--Shares used in computing diluted net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding contextRef="c20160101to20161231" unitRef="U002" decimals="-3">120933000</us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding>
  <!--Shares used in computing diluted net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding contextRef="c20170101to20171231" unitRef="U002" decimals="-3">126098000</us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding>
  <!--Shares used in computing diluted net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding contextRef="c20181001to20181231" unitRef="U002" decimals="-3">149856000</us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding>
  <!--Shares used in computing diluted net income (loss) per share (in shares)-->
  <us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding contextRef="c20170101to20170331" unitRef="U002" decimals="-3">124972000</us-gaap:WeightedAverageNumberOfDilutedSharesOutstanding>
  <!--Period after billing when payment is received-->
  <ions:PeriodAfterBillingWhenPaymentIsReceived contextRef="c20180101to20181231">P3M</ions:PeriodAfterBillingWhenPaymentIsReceived>
  <!--Number of agreements with collaboration partner-Biogen Inc. [Member]-->
  <ions:NumberOfAgreementsWithCollaborationPartner contextRef="c20180401to20180630_MajorCustomersAxis_BiogenIncMember" unitRef="U006" decimals="INF">2</ions:NumberOfAgreementsWithCollaborationPartner>
  <!--New Accounting Pronouncement or Change in Accounting Principle, Effect of Change on Revenue from amortization of payments using input method-Research and Development Revenue Under Collaborative Agreements [Member]-->
  <ions:NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod contextRef="c20160101to20161231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" unitRef="U001" decimals="-6">0</ions:NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod>
  <!--New Accounting Pronouncement or Change in Accounting Principle, Effect of Change on Revenue from amortization of payments using input method-Research and Development Revenue Under Collaborative Agreements [Member]-->
  <ions:NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod contextRef="c20170101to20171231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" unitRef="U001" decimals="-5">-15100000</ions:NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod>
  <!--New Accounting Pronouncement or Change in Accounting Principle, Effect of Change on Revenue from amortization of milestone payments achieved under new revenue guidance-Research and Development Revenue Under Collaborative Agreements [Member]-->
  <ions:NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance contextRef="c20160101to20161231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" unitRef="U001" decimals="-5">24100000</ions:NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance>
  <!--New Accounting Pronouncement or Change in Accounting Principle, Effect of Change on Revenue from amortization of milestone payments achieved under new revenue guidance-Research and Development Revenue Under Collaborative Agreements [Member]-->
  <ions:NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance contextRef="c20170101to20171231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" unitRef="U001" decimals="-5">23700000</ions:NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance>
  <!--Number of antisense drugs in development-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-->
  <ions:NumberOfAntisenseDrugsInDevelopment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" unitRef="U012" decimals="INF">2</ions:NumberOfAntisenseDrugsInDevelopment>
  <!--Payment receivable under license agreement-Collaborative Arrangement and Licensing Agreement Entered Into in August 2018 with PTC Therapeutics [Member]-Akcea Therapeutics, Inc. [Member]-->
  <ions:PaymentReceivableUnderLicenseAgreement contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" unitRef="U001" decimals="-6">26000000</ions:PaymentReceivableUnderLicenseAgreement>
  <!--Period before collaboration partner pays royalties on net sales of product after first commercial sale in Brazil-Akcea Therapeutics, Inc. [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in August 2018 with PTC Therapeutics [Member]-->
  <ions:PeriodBeforeCollaborationPartnerPaysRoyaltiesOnNetSalesOfProductAfterFirstCommercialSaleInBrazil contextRef="c20180101to20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember">P12M</ions:PeriodBeforeCollaborationPartnerPaysRoyaltiesOnNetSalesOfProductAfterFirstCommercialSaleInBrazil>
  <!--Royalty percentage received on net sales of each drug in Latin America from collaboration partner-Akcea Therapeutics, Inc. [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in August 2018 with PTC Therapeutics [Member]-->
  <ions:RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner contextRef="c20180101to20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" unitRef="U003" decimals="1">0.2</ions:RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner>
  <!--Revenue recognized by collaboration partner in Latin America before paying royalties-Akcea Therapeutics, Inc. [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in August 2018 with PTC Therapeutics [Member]-->
  <ions:RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties contextRef="c20180101to20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" unitRef="U001" decimals="-6">10000000</ions:RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties>
  <!--Payment receivable under license agreement to be paid after approval-Collaborative Arrangement and Licensing Agreement Entered Into in August 2018 with PTC Therapeutics [Member]-Akcea Therapeutics, Inc. [Member]-->
  <ions:PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" unitRef="U001" decimals="-6">6000000</ions:PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval>
  <!--Potential premium received if common stock is purchased in the future-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture contextRef="c20170331_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-5">5000000</ions:PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture>
  <!--Portion of upfront payment retained-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-Akcea Therapeutics, Inc. [Member]-->
  <ions:PortionOfUpfrontPaymentRetained contextRef="c20170101to20170331_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">60000000</ions:PortionOfUpfrontPaymentRetained>
  <!--Premium received on shares issued-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:PremiumReceivedOnSharesIssued contextRef="c20170101to20170331_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-5">28400000</ions:PremiumReceivedOnSharesIssued>
  <!--Maximum amount of payments receivable for milestones-Akcea Therapeutics, Inc. [Member]-AKCEA-APO(a)-L [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForMilestones contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_ProductOrServiceAxis_AKCEAAPOALMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">675000000</ions:MaximumAmountOfPaymentsReceivableForMilestones>
  <!--Maximum amount of payments receivable for milestones-Akcea Therapeutics, Inc. [Member]-AKCEA-APOCIII-L [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForMilestones contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_ProductOrServiceAxis_AKCEAAPOCIIILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">530000000</ions:MaximumAmountOfPaymentsReceivableForMilestones>
  <!--Percentage of license fees, milestone payments and royalties paid as sublicense fee-Akcea Therapeutics, Inc. [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee contextRef="c20180101to20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U003" decimals="INF">0.5</ions:PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee>
  <!--Portion of upfront payment paid as a sublicense fee-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-Akcea Therapeutics, Inc. [Member]-->
  <ions:PortionOfUpfrontPaymentPaidAsASublicenseFee contextRef="c20170101to20170331_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">15000000</ions:PortionOfUpfrontPaymentPaidAsASublicenseFee>
  <!--Royalty percentage received on sales of drug-AKCEA-APO(a)-L [Member]-Akcea Therapeutics, Inc. [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:RoyaltyPercentageReceivedOnSalesOfDrug contextRef="c20180101to20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_ProductOrServiceAxis_AKCEAAPOALMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U003" decimals="1">0.2</ions:RoyaltyPercentageReceivedOnSalesOfDrug>
  <!--Royalty percentage received on sales of drug-AKCEA-APOCIII-L [Member]-Akcea Therapeutics, Inc. [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:RoyaltyPercentageReceivedOnSalesOfDrug contextRef="c20180101to20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_ProductOrServiceAxis_AKCEAAPOCIIILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U003" decimals="1">0.2</ions:RoyaltyPercentageReceivedOnSalesOfDrug>
  <!--License fee receivable per drug-Akcea Therapeutics, Inc. [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:LicenseFeePaidPerDrug contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">150000000</ions:LicenseFeePaidPerDrug>
  <!--Proceeds from sale of common stock, including premium paid-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:ProceedsFromSaleOfCommonStockIncludingPremiumPaid contextRef="c20170101to20170331_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">100000000</ions:ProceedsFromSaleOfCommonStockIncludingPremiumPaid>
  <!--Number of obligations fully satisfied-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-->
  <ions:NumberOfObligationsFullySatisified contextRef="c20140331_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U005" decimals="INF">3</ions:NumberOfObligationsFullySatisified>
  <!--Number of drugs that can be licensed under option in collaboration agreements-Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]-->
  <ions:NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" unitRef="U012" decimals="INF">3</ions:NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements>
  <!--Number of programs advanced-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-->
  <ions:NumberOfProgramsAdvanced contextRef="c20181001to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U015" decimals="INF">2</ions:NumberOfProgramsAdvanced>
  <!--Revenue from Contract with Customer, Transaction Price, Additions-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPriceAdditions contextRef="c20170701to20170930_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U001" decimals="-6">10000000</ions:RevenueFromContractWithCustomerTransactionPriceAdditions>
  <!--Revenue from Contract with Customer, Transaction Price, Additions-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPriceAdditions contextRef="c20181001to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U001" decimals="-6">15000000</ions:RevenueFromContractWithCustomerTransactionPriceAdditions>
  <!--Number of countries where drug is approved for use-Collaborative Arrangement and Licensing Agreement Entered Into in January 2012 with Biogen [Member]-Minimum [Member]-->
  <ions:NumberOfCountriesWhereDrugIsApprovedForUse contextRef="c20181231_RangeAxis_MinimumMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" unitRef="U013" decimals="INF">40</ions:NumberOfCountriesWhereDrugIsApprovedForUse>
  <!--Cumulative Revenue from Contract with Customer, Excluding Assessed Tax-Research and Development Revenue Under Collaborative Agreements [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2012 with Biogen [Member]-->
  <ions:CumulativeRevenueFromContractWithCustomerExcludingAssessedTax contextRef="c20181231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" unitRef="U001" decimals="-6">435000000</ions:CumulativeRevenueFromContractWithCustomerExcludingAssessedTax>
  <!--Cumulative Revenue from Contract with Customer, Excluding Assessed Tax-Collaborative Arrangement and Licensing Agreement Entered Into in January 2012 with Biogen [Member]-SPINRAZA Royalties [Member]-->
  <ions:CumulativeRevenueFromContractWithCustomerExcludingAssessedTax contextRef="c20181231_ProductOrServiceAxis_SPINRAZARoyaltiesMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" unitRef="U001" decimals="-6">350000000</ions:CumulativeRevenueFromContractWithCustomerExcludingAssessedTax>
  <!--Cumulative Revenue from Contract with Customer, Excluding Assessed Tax-Collaborative Arrangement and Licensing Agreement Entered Into in January 2012 with Biogen [Member]-->
  <ions:CumulativeRevenueFromContractWithCustomerExcludingAssessedTax contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" unitRef="U001" decimals="-6">785000000</ions:CumulativeRevenueFromContractWithCustomerExcludingAssessedTax>
  <!--Maximum amount of payments receivable per drug or program for regulatory milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U001" decimals="-6">130000000</ions:MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones>
  <!--Maximum amount of payments receivable per drug or program for regulatory milestones-Collaborative Arrangement and Licensing Agreement Entered Into in August 2018 with PTC Therapeutics [Member]-Akcea Therapeutics, Inc. [Member]-->
  <ions:MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" unitRef="U001" decimals="-6">8000000</ions:MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones>
  <!--Number of additional drugs in clinical development to treat neurodegenerative diseases-Collaborative Arrangements and Licensing Agreements, Biogen [Member]-->
  <ions:NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementsAndLicensingAgreementsBiogenMember" unitRef="U012" decimals="INF">6</ions:NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases>
  <!--Payments included in transaction price for performance obligation-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-Research and Development Revenue Under Collaborative Agreements [Member]-->
  <ions:PaymentsIncludedInTransactionPriceForPerformanceObligation contextRef="c20181231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U001" decimals="-6">40000000</ions:PaymentsIncludedInTransactionPriceForPerformanceObligation>
  <!--Payments included in transaction price for performance obligation-Research and Development Revenue Under Collaborative Agreements [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]-->
  <ions:PaymentsIncludedInTransactionPriceForPerformanceObligation contextRef="c20181231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" unitRef="U001" decimals="-6">145000000</ions:PaymentsIncludedInTransactionPriceForPerformanceObligation>
  <!--Payments included in transaction price for performance obligation-Research and Development Revenue Under Collaborative Agreements [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]-->
  <ions:PaymentsIncludedInTransactionPriceForPerformanceObligation contextRef="c20181231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" unitRef="U001" decimals="-6">90000000</ions:PaymentsIncludedInTransactionPriceForPerformanceObligation>
  <!--Term of collaboration agreement-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:TermOfCollaborationAgreement contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember">P10Y</ions:TermOfCollaborationAgreement>
  <!--Maximum amount of payments receivable per drug or program for license fees and substantive milestone payments-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U001" decimals="-6">210000000</ions:MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments>
  <!--Upfront payment received, including purchase of stock-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:UpfrontPaymentReceivedIncludingPurchaseOfStock contextRef="c20180401to20180630_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U001" decimals="-9">1000000000</ions:UpfrontPaymentReceivedIncludingPurchaseOfStock>
  <!--Maximum amount of payments receivable for sales milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2017 with Biogen [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForSalesMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" unitRef="U001" decimals="-6">800000000</ions:MaximumAmountOfPaymentsReceivableForSalesMilestones>
  <!--Number of targets-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:NumberOfTargets contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U014" decimals="INF">2</ions:NumberOfTargets>
  <!--Number of targets-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:NumberOfTargets contextRef="c20121231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U014" decimals="INF">3</ions:NumberOfTargets>
  <!--Maximum amount of payments receivable per drug or program for development milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U001" decimals="-6">10000000</ions:MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones>
  <!--Premium paid on shares purchased-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:PremiumPaidOnSharesPurchased contextRef="c20180401to20180630_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U001" decimals="-6">177000000</ions:PremiumPaidOnSharesPurchased>
  <!--Number of drugs currently being advanced-Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]-->
  <ions:NumberOfDrugsCurrentlyBeingAdvanced contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" unitRef="U012" decimals="INF">5</ions:NumberOfDrugsCurrentlyBeingAdvanced>
  <!--Percentage cash premium paid on shares purchased-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:PercentageCashPremiumPaidOnSharesPurchased contextRef="c20180401to20180630_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U003" decimals="2">0.25</ions:PercentageCashPremiumPaidOnSharesPurchased>
  <!--Next potential payment-Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]-->
  <ions:NextPotentialPayment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" unitRef="U001" decimals="-6">10000000</ions:NextPotentialPayment>
  <!--Next potential payment-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:NextPotentialPayment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U001" decimals="-5">7500000</ions:NextPotentialPayment>
  <!--Next potential payment-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:NextPotentialPayment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U001" decimals="-5">7500000</ions:NextPotentialPayment>
  <!--Next potential payment-Collaborative Arrangement and Licensing Agreement Entered Into in December 2017 with Biogen [Member]-->
  <ions:NextPotentialPayment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" unitRef="U001" decimals="-6">60000000</ions:NextPotentialPayment>
  <!--Next potential payment-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-->
  <ions:NextPotentialPayment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U001" decimals="-5">25000000</ions:NextPotentialPayment>
  <!--Next potential payment-Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]-->
  <ions:NextPotentialPayment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" unitRef="U001" decimals="-6">10000000</ions:NextPotentialPayment>
  <!--Maximum amount of payments receivable per drug for substantive milestone payments-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U001" decimals="-6">270000000</ions:MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments>
  <!--Number of programs under which drugs are to be developed and commercialized-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized contextRef="c20121231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U015" decimals="INF">3</ions:NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized>
  <!--Number of programs under which drugs are to be developed and commercialized-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <ions:NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized contextRef="c20141231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" unitRef="U015" decimals="INF">3</ions:NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized>
  <!--Minimum amount of payments receivable for license fees and substantive milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-->
  <ions:MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U001" decimals="-6">450000000</ions:MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones>
  <!--Minimum amount of payments receivable for license fees and substantive milestones-Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]-->
  <ions:MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" unitRef="U001" decimals="-9">4000000000</ions:MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones>
  <!--Minimum amount of payments receivable for license fees and substantive milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <ions:MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" unitRef="U001" decimals="-6">800000000</ions:MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones>
  <!--Revenue from Contract with Customer, Number of new performance obligations-Collaborative Arrangement and Licensing Agreement Amended in February 2017 with Bayer [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfNewPerformanceObligations contextRef="c20170201to20170228_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" unitRef="U005" decimals="INF">2</ions:RevenueFromContractWithCustomerNumberOfNewPerformanceObligations>
  <!--Revenue from Contract with Customer, Number of new performance obligations-Collaborative Arrangement and Licensing Agreement Amended in February 2017 with Bayer [Member]-IONIS-FXI-L [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfNewPerformanceObligations contextRef="c20170201to20170228_ProductOrServiceAxis_IONISFXILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfNewPerformanceObligations>
  <!--Revenue from Contract with Customer, Number of new performance obligations-Collaborative Arrangement and Licensing Agreement Amended in February 2017 with Bayer [Member]-Research and Development Services for IONIS-FXI-L [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfNewPerformanceObligations contextRef="c20170201to20170228_ProductOrServiceAxis_ResearchAndDevelopmentServicesForIONISFXILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfNewPerformanceObligations>
  <!--Royalty percentage received on gross margins of drugs under collaboration agreement-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U003" decimals="1">0.2</ions:RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement>
  <!--Payment received for advancing programs-Collaborative Arrangement and Licensing Agreement Amended in February 2017 with Bayer [Member]-->
  <ions:PaymentReceivedForAdvancingPrograms contextRef="c20170201to20170228_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" unitRef="U001" decimals="-6">75000000</ions:PaymentReceivedForAdvancingPrograms>
  <!--Maximum amount of payments receivable for commercialization milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2017 with Biogen [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" unitRef="U001" decimals="-6">180000000</ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones>
  <!--Maximum amount of payments receivable for commercialization milestones-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-6">110000000</ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones>
  <!--Maximum amount of payments receivable for commercialization milestones-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" unitRef="U001" decimals="-6">70000000</ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones>
  <!--Maximum amount of payments receivable for commercialization milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" unitRef="U001" decimals="-6">180000000</ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones>
  <!--Maximum amount of payments receivable for commercialization milestones-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-6">80000000</ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones>
  <!--Maximum amount of payments receivable for commercialization milestones-Akcea Therapeutics, Inc. [Member]-AKCEA-APO(a)-L [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_ProductOrServiceAxis_AKCEAAPOALMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">360000000</ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones>
  <!--Maximum amount of payments receivable for commercialization milestones-Akcea Therapeutics, Inc. [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-AKCEA-APOCIII-L [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_ProductOrServiceAxis_AKCEAAPOCIIILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">265000000</ions:MaximumAmountOfPaymentsReceivableForCommercializationMilestones>
  <!--Next potential milestone payment-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:NextPotentialMilestonePayment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-6">10000000</ions:NextPotentialMilestonePayment>
  <!--Next potential milestone payment-Maximum [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-->
  <ions:NextPotentialMilestonePayment contextRef="c20181231_RangeAxis_MaximumMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" unitRef="U001" decimals="-6">25000000</ions:NextPotentialMilestonePayment>
  <!--Next potential milestone payment-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <ions:NextPotentialMilestonePayment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" unitRef="U001" decimals="-6">5000000</ions:NextPotentialMilestonePayment>
  <!--Next potential milestone payment-Collaborative Arrangement and Licensing Agreement Entered Into in October 2018 with Roche [Member]-->
  <ions:NextPotentialMilestonePayment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" unitRef="U001" decimals="-6">20000000</ions:NextPotentialMilestonePayment>
  <!--Next potential milestone payment-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:NextPotentialMilestonePayment contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-6">15000000</ions:NextPotentialMilestonePayment>
  <!--Maximum amount of payments receivable for development milestones-Antisense Molecule [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones contextRef="c20181231_ProductOrServiceAxis_AntisenseMoleculeMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" unitRef="U001" decimals="-6">60000000</ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones>
  <!--Maximum amount of payments receivable for development milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2017 with Biogen [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" unitRef="U001" decimals="-6">80000000</ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones>
  <!--Maximum amount of payments receivable for development milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U001" decimals="-6">152000000</ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones>
  <!--Maximum amount of payments receivable for development milestones-Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" unitRef="U001" decimals="-8">1100000000</ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones>
  <!--Maximum amount of payments receivable for development milestones-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-6">125000000</ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones>
  <!--Maximum amount of payments receivable for development milestones-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" unitRef="U001" decimals="-5">47500000</ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones>
  <!--Maximum amount of payments receivable for development milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" unitRef="U001" decimals="-6">175000000</ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones>
  <!--Maximum amount of payments receivable for development milestones-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-6">70000000</ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones>
  <!--Maximum amount of payments receivable for development milestones-Akcea Therapeutics, Inc. [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-AKCEA-APOCIII-L [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_ProductOrServiceAxis_AKCEAAPOCIIILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">25000000</ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones>
  <!--Maximum amount of payments receivable for development milestones-Akcea Therapeutics, Inc. [Member]-AKCEA-APO(a)-L [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_ProductOrServiceAxis_AKCEAAPOALMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">25000000</ions:MaximumAmountOfPaymentsReceivableForDevelopmentMilestones>
  <!--Milestone payments received-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:MilestonePaymentsReceived contextRef="c20170101to20171231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-6">3000000</ions:MilestonePaymentsReceived>
  <!--Maximum amount of payments receivable for license fees and substantive milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2017 with Biogen [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" unitRef="U001" decimals="-8">1200000000</ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones>
  <!--Maximum amount of payments receivable for license fees and substantive milestones-Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]-Antisense Molecule [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones contextRef="c20181231_ProductOrServiceAxis_AntisenseMoleculeMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" unitRef="U001" decimals="-6">260000000</ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones>
  <!--Maximum amount of payments receivable for license fees and substantive milestones-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-6">385000000</ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones>
  <!--Maximum amount of payments receivable for license fees and substantive milestones-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" unitRef="U001" decimals="-6">262000000</ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones>
  <!--Maximum amount of payments receivable for license fees and substantive milestones-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-6">365000000</ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones>
  <!--Maximum amount of payments receivable for license fees and substantive milestones-Collaborative Arrangement and Licensing Agreement Entered Into in October 2018 with Roche [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" unitRef="U001" decimals="-6">684000000</ions:MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones>
  <!--Upfront payment received-Subsequent Event [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20190101to20190301_SubsequentEventTypeAxis_SubsequentEventMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-6">35000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20150501to20150531_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-6">100000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in October 2018 with Roche [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20181001to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" unitRef="U001" decimals="-6">75000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20180401to20180630_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U001" decimals="-6">375000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20130901to20130930_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" unitRef="U001" decimals="-6">100000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20121201to20121231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U001" decimals="-6">30000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in December 2017 with Biogen [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20171201to20171231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" unitRef="U001" decimals="-6">25000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20121201to20121231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U001" decimals="-6">31000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20150701to20150731_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" unitRef="U001" decimals="-6">65000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20150401to20150630_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-6">100000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20100301to20100331_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" unitRef="U001" decimals="-6">35000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20141201to20141231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" unitRef="U001" decimals="-6">35000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20130401to20130430_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-6">30000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in October 2018 with Roche [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20181001to20181031_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" unitRef="U001" decimals="-6">75000000</ions:UpfrontPaymentReceived>
  <!--Upfront payment received-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-Akcea Therapeutics, Inc. [Member]-->
  <ions:UpfrontPaymentReceived contextRef="c20170101to20170331_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">75000000</ions:UpfrontPaymentReceived>
  <!--Maximum amount of payments receivable for regulatory milestones-Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]-Antisense Molecule [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones contextRef="c20181231_ProductOrServiceAxis_AntisenseMoleculeMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" unitRef="U001" decimals="-6">130000000</ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones>
  <!--Maximum amount of payments receivable for regulatory milestones-Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" unitRef="U001" decimals="-8">2900000000</ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones>
  <!--Maximum amount of payments receivable for regulatory milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U001" decimals="-6">275000000</ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones>
  <!--Maximum amount of payments receivable for regulatory milestones-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" unitRef="U001" decimals="-6">120000000</ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones>
  <!--Maximum amount of payments receivable for regulatory milestones-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" unitRef="U001" decimals="-6">440000000</ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones>
  <!--Maximum amount of payments receivable for regulatory milestones-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-6">170000000</ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones>
  <!--Maximum amount of payments receivable for regulatory milestones-Akcea Therapeutics, Inc. [Member]-AKCEA-APOCIII-L [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_ProductOrServiceAxis_AKCEAAPOCIIILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">240000000</ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones>
  <!--Maximum amount of payments receivable for regulatory milestones-AKCEA-APO(a)-L [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-Akcea Therapeutics, Inc. [Member]-->
  <ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones contextRef="c20181231_ConsolidatedEntitiesAxis_AkceaTherapeuticsIncMember_ProductOrServiceAxis_AKCEAAPOALMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-6">290000000</ions:MaximumAmountOfPaymentsReceivableForRegulatoryMilestones>
  <!--Cumulative payments received-Collaborative Arrangements and Licensing Agreements, Biogen [Member]-->
  <ions:CumulativePaymentsReceived contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementsAndLicensingAgreementsBiogenMember" unitRef="U001" decimals="-8">2000000000</ions:CumulativePaymentsReceived>
  <!--Cumulative payments received-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:CumulativePaymentsReceived contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U001" decimals="-9">1000000000</ions:CumulativePaymentsReceived>
  <!--Cumulative payments received-Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]-->
  <ions:CumulativePaymentsReceived contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" unitRef="U001" decimals="-6">210000000</ions:CumulativePaymentsReceived>
  <!--Cumulative payments received-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:CumulativePaymentsReceived contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U001" decimals="-6">58000000</ions:CumulativePaymentsReceived>
  <!--Cumulative payments received-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-->
  <ions:CumulativePaymentsReceived contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U001" decimals="-6">125000000</ions:CumulativePaymentsReceived>
  <!--Cumulative payments received-Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]-->
  <ions:CumulativePaymentsReceived contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" unitRef="U001" decimals="-6">165000000</ions:CumulativePaymentsReceived>
  <!--Cumulative payments received-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:CumulativePaymentsReceived contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-6">175000000</ions:CumulativePaymentsReceived>
  <!--Cumulative payments received-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-Minimum [Member]-->
  <ions:CumulativePaymentsReceived contextRef="c20181231_RangeAxis_MinimumMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" unitRef="U001" decimals="-6">162000000</ions:CumulativePaymentsReceived>
  <!--Cumulative payments received-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <ions:CumulativePaymentsReceived contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" unitRef="U001" decimals="-6">75000000</ions:CumulativePaymentsReceived>
  <!--Cumulative payments received-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:CumulativePaymentsReceived contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-6">112000000</ions:CumulativePaymentsReceived>
  <!--Royalty percentage received on net sales of drug-Maximum [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2012 with Biogen [Member]-->
  <ions:RoyaltyPercentageReceivedOnNetSalesOfDrug contextRef="c20180101to20181231_RangeAxis_MaximumMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" unitRef="U003" decimals="2">0.15</ions:RoyaltyPercentageReceivedOnNetSalesOfDrug>
  <!--Royalty percentage received on net sales of drug-Collaborative Arrangement and Licensing Agreement Entered Into in January 2012 with Biogen [Member]-Minimum [Member]-->
  <ions:RoyaltyPercentageReceivedOnNetSalesOfDrug contextRef="c20180101to20181231_RangeAxis_MinimumMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" unitRef="U003" decimals="2">0.11</ions:RoyaltyPercentageReceivedOnNetSalesOfDrug>
  <!--Royalty percentage received on net sales of drug-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:RoyaltyPercentageReceivedOnNetSalesOfDrug contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U003" decimals="1">0.2</ions:RoyaltyPercentageReceivedOnNetSalesOfDrug>
  <!--Royalty percentage received on net sales of drug-Collaborative Arrangement and Licensing Agreement Entered Into in December 2017 with Biogen [Member]-->
  <ions:RoyaltyPercentageReceivedOnNetSalesOfDrug contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" unitRef="U003" decimals="1">0.2</ions:RoyaltyPercentageReceivedOnNetSalesOfDrug>
  <!--Royalty percentage received on net sales of drug-Collaborative Arrangement and Licensing Agreement Entered Into in October 2018 with Roche [Member]-->
  <ions:RoyaltyPercentageReceivedOnNetSalesOfDrug contextRef="c20180101to20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" unitRef="U003" decimals="1">0.2</ions:RoyaltyPercentageReceivedOnNetSalesOfDrug>
  <!--Maximum amount of payment receivable for each additional drug developed-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped contextRef="c20181231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-5">136500000</ions:MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Amended in February 2017 with Bayer [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20170228_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" unitRef="U005" decimals="INF">3</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in January 2012 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20161231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" unitRef="U005" decimals="INF">2</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20180430_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in December 2017 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20171231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20121231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20130930_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20150731_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20121231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U005" decimals="INF">4</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20150531_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U005" decimals="INF">3</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20100331_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20141231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20130430_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in October 2018 with Roche [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20181031_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" unitRef="U005" decimals="INF">1</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20170331_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U005" decimals="INF">4</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Number of separate performance obligations-Collaborative Arrangement and Licensing Agreement Entered Into in August 2018 with PTC Therapeutics [Member]-->
  <ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations contextRef="c20180831_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" unitRef="U005" decimals="INF">2</ions:RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Amended in February 2017 with Bayer [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20170228_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" unitRef="U001" decimals="-6">75000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20121231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" unitRef="U001" decimals="-6">30000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20130930_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" unitRef="U001" decimals="-6">100000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in December 2017 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20171231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" unitRef="U001" decimals="-6">25000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20180430_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" unitRef="U001" decimals="-6">552000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-Research and Development Revenue Under Collaborative Agreements [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20121231_ProductOrServiceAxis_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U001" decimals="-5">7600000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with AstraZeneca [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20121231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" unitRef="U001" decimals="-6">31000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20150731_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" unitRef="U001" decimals="-6">65000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-Research and Development Services for IONIS-FXI [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20150531_ProductOrServiceAxis_ResearchAndDevelopmentServicesForIONISFXIMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-5">4300000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-IONIS-FXI [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20150531_ProductOrServiceAxis_IONISFXIMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-5">91200000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-IONIS-FXI-L [Member]-Collaborative Arrangement and Licensing Agreement Amended in February 2017 with Bayer [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20170228_ProductOrServiceAxis_IONISFXILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" unitRef="U001" decimals="-5">64900000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20150531_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-6">100000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-Research and Development Services for IONIS-FXI-L [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20170228_ProductOrServiceAxis_ResearchAndDevelopmentServicesForIONISFXILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-5">10100000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-IONIS-FXI Active Pharmaceutical Ingredient [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20150531_ProductOrServiceAxis_IONISFXIActivePharmaceuticalIngredientMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" unitRef="U001" decimals="-5">4500000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in March 2010 with GSK [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20100331_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" unitRef="U001" decimals="-6">35000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in December 2014 with Janssen Biotech, Inc. [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20141231_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" unitRef="U001" decimals="-6">35000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20130430_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" unitRef="U001" decimals="-6">30000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in October 2018 with Roche [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20181031_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" unitRef="U001" decimals="-6">75000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20170331_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-5">108400000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-Delivery of AKCEA-APO(a)-L [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20170331_ProductOrServiceAxis_DeliveryOfAKCEAAPOALMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-5">1500000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Research and Development Services for AKCEA-APO(a)-L [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20170331_ProductOrServiceAxis_ResearchAndDevelopmentServicesForAKCEAAPOALMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-5">64000000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-Research and Development Services for AKCEA-APOCIII-L [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20170331_ProductOrServiceAxis_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-5">40100000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Revenue from Contract with Customer, Transaction Price-Delivery of AKCEA-APOCIII-L [Member]-Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]-->
  <ions:RevenueFromContractWithCustomerTransactionPrice contextRef="c20170331_ProductOrServiceAxis_DeliveryOfAKCEAAPOCIIILMember_TypeOfArrangementAxis_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" unitRef="U001" decimals="-5">2800000</ions:RevenueFromContractWithCustomerTransactionPrice>
  <!--Accrued in-licensing fees, Current-->
  <ions:AccruedInLicensingFeesCurrent contextRef="c20181231" unitRef="U001" decimals="-3">12298000</ions:AccruedInLicensingFeesCurrent>
  <!--Accrued in-licensing fees, Current-->
  <ions:AccruedInLicensingFeesCurrent contextRef="c20171231" unitRef="U001" decimals="-3">33790000</ions:AccruedInLicensingFeesCurrent>
  <!--Accrued clinical expenses-->
  <ions:AccruedClinicalExpenses contextRef="c20181231" unitRef="U001" decimals="-3">22125000</ions:AccruedClinicalExpenses>
  <!--Accrued clinical expenses-->
  <ions:AccruedClinicalExpenses contextRef="c20171231" unitRef="U001" decimals="-3">16347000</ions:AccruedClinicalExpenses>
  <!--Number of Significant Partners-Accounts Receivable [Member]-Credit Concentration [Member]-Significant Partners [Member]-->
  <ions:NumberOfSignificantPartners contextRef="c20170101to20171231_ConcentrationRiskByBenchmarkAxis_AccountsReceivableMember_ConcentrationRiskByTypeAxis_CreditConcentrationRiskMember_MajorCustomersAxis_SignificantPartnersMember" unitRef="U016" decimals="INF">2</ions:NumberOfSignificantPartners>
  <!--Number of Significant Partners-Accounts Receivable [Member]-Credit Concentration [Member]-Significant Partners [Member]-->
  <ions:NumberOfSignificantPartners contextRef="c20180101to20181231_ConcentrationRiskByBenchmarkAxis_AccountsReceivableMember_ConcentrationRiskByTypeAxis_CreditConcentrationRiskMember_MajorCustomersAxis_SignificantPartnersMember" unitRef="U016" decimals="INF">4</ions:NumberOfSignificantPartners>
  <!--Loss Contingencies, Past sales of medication included in award-Suit Related to U.S. Patents [Member]-->
  <ions:LossContingenciesPastSalesOfMedicationIncludedInAward contextRef="c20160301to20160331_LitigationCaseAxis_SuitRelatedToUSPatentsMember" unitRef="U001" decimals="-9">5000000000</ions:LossContingenciesPastSalesOfMedicationIncludedInAward>
  <!--Loss Contingencies, Percentage applied to past sales of medication included in award-Suit Related to U.S. Patents [Member]-->
  <ions:LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward contextRef="c20160301to20160331_LitigationCaseAxis_SuitRelatedToUSPatentsMember" unitRef="U003" decimals="INF">0.04</ions:LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward>
  <!--Loss Contingencies, Number of additional non-jury defenses asserted-Suit Related to U.S. Patents [Member]-->
  <ions:LossContingenciesNumberOfAdditionalNonJuryDefensesAsserted contextRef="c20160301to20160331_LitigationCaseAxis_SuitRelatedToUSPatentsMember" unitRef="U018" decimals="INF">2</ions:LossContingenciesNumberOfAdditionalNonJuryDefensesAsserted>
  <!--Defined Contribution Plan, Employee Contribution Limit by Plan Participants over Fifty Years Age-->
  <ions:DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge contextRef="c20180101to20181231" unitRef="U001" decimals="0">24500</ions:DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge>
  <!--Defined Contribution Plan, Employee Contribution Limit by Plan Participants under Fifty Years Age-->
  <ions:DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge contextRef="c20180101to20181231" unitRef="U001" decimals="0">18500</ions:DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge>
  <!--Incremental Common Shares Attributable to Dilutive Effect of Employee Stock Purchase Plan-->
  <ions:IncrementalCommonSharesAttributableToDilutiveEffectOfEmployeeStockPurchasePlan contextRef="c20170101to20170331" unitRef="U002" decimals="-3">60000</ions:IncrementalCommonSharesAttributableToDilutiveEffectOfEmployeeStockPurchasePlan>
  <!--Incremental Common Shares Attributable to Dilutive Effect of Employee Stock Purchase Plan-->
  <ions:IncrementalCommonSharesAttributableToDilutiveEffectOfEmployeeStockPurchasePlan contextRef="c20181001to20181231" unitRef="U002" decimals="-3">7000</ions:IncrementalCommonSharesAttributableToDilutiveEffectOfEmployeeStockPurchasePlan>
  <!--Available-for-sale Securities, Debt Maturities, after One Through Two Years, Percentage-->
  <ions:AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage contextRef="c20181231" unitRef="U003" decimals="1">0.2</ions:AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage>
  <!--Number of Publicly-Held Companies in which Entity has Equity Investment-->
  <ions:NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment contextRef="c20181231" unitRef="U007" decimals="INF">2</ions:NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment>
  <!--Available-for-sale Securities, Debt Maturities, within One Year, Percentage-->
  <ions:AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage contextRef="c20181231" unitRef="U003" decimals="2">0.77</ions:AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage>
  <!--Available-for-sale Securities, Debt Maturities, Total, Percentage-->
  <ions:AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage contextRef="c20181231" unitRef="U003" decimals="INF">1</ions:AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage>
  <!--Number of Privately-Held Companies in which Entity has Equity Investment-->
  <ions:NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment contextRef="c20181231" unitRef="U007" decimals="INF">4</ions:NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment>
  <!--Available-for-sale Securities, Debt Maturities, within Two Years, Percentage-->
  <ions:AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage contextRef="c20181231" unitRef="U003" decimals="2">0.97</ions:AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage>
  <!--Available-for-sale Securities, Debt Maturities, after Two Through Three and One Half Years, Percentage-->
  <ions:AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage contextRef="c20181231" unitRef="U003" decimals="2">0.03</ions:AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage>
  <!--Maximum contract maturity period, range 3-->
  <ions:MaximumContractMaturityPeriodRange3 contextRef="c20180101to20181231">P3Y6M</ions:MaximumContractMaturityPeriodRange3>
  <!--Maximum contract maturity period, range 1-->
  <ions:MaximumContractMaturityPeriodRange1 contextRef="c20180101to20181231">P1Y</ions:MaximumContractMaturityPeriodRange1>
  <!--Maximum contract maturity period, range 2-->
  <ions:MaximumContractMaturityPeriodRange2 contextRef="c20180101to20181231">P2Y</ions:MaximumContractMaturityPeriodRange2>
  <!--Patent Expenses-Patents [Member]-->
  <ions:PatentExpenses contextRef="c20160101to20161231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">3900000</ions:PatentExpenses>
  <!--Patent Expenses-Patents [Member]-->
  <ions:PatentExpenses contextRef="c20170101to20171231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">2100000</ions:PatentExpenses>
  <!--Patent Expenses-Patents [Member]-->
  <ions:PatentExpenses contextRef="c20180101to20181231_FiniteLivedIntangibleAssetsByMajorClassAxis_PatentsMember" unitRef="U001" decimals="-5">2600000</ions:PatentExpenses>
  <!--Stock Issued During Period, Shares, New Issues by Subsidiary-Common Stock [Member]-->
  <ions:StockIssuedDuringPeriodSharesNewIssuesBySubsidiary contextRef="c20170101to20171231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U002" decimals="-3">0</ions:StockIssuedDuringPeriodSharesNewIssuesBySubsidiary>
  <!--Noncontrolling Interest, Increase from New Issues by Subsidiary-Noncontrolling Interest in Akcea Therapeutics, Inc. [Member]-->
  <ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary contextRef="c20170101to20171231_StatementEquityComponentsAxis_NoncontrollingInterestMember" unitRef="U001" decimals="-3">90381000</ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary>
  <!--Noncontrolling Interest, Increase from New Issues by Subsidiary-Total Ionis Stockholders' Equity [Member]-->
  <ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary contextRef="c20170101to20171231_StatementEquityComponentsAxis_ParentMember" unitRef="U001" decimals="-3">-90351000</ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary>
  <!--Noncontrolling Interest, Increase from New Issues by Subsidiary-Common Stock [Member]-->
  <ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary contextRef="c20170101to20171231_StatementEquityComponentsAxis_CommonStockMember" unitRef="U001" decimals="-3">0</ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary>
  <!--Noncontrolling Interest, Increase from New Issues by Subsidiary-Retained Earnings [Member]-->
  <ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary contextRef="c20170101to20171231_StatementEquityComponentsAxis_RetainedEarningsMember" unitRef="U001" decimals="-3">0</ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary>
  <!--Noncontrolling Interest, Increase from New Issues by Subsidiary-Accumulated Other Comprehensive Loss [Member]-->
  <ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary contextRef="c20170101to20171231_StatementEquityComponentsAxis_AccumulatedOtherComprehensiveIncomeMember" unitRef="U001" decimals="-3">0</ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary>
  <!--Noncontrolling Interest, Increase from New Issues by Subsidiary-Additional Paid In Capital [Member]-->
  <ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary contextRef="c20170101to20171231_StatementEquityComponentsAxis_AdditionalPaidInCapitalMember" unitRef="U001" decimals="-3">-90351000</ions:NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary>
  <!--Noncontrolling Interest, Increase from New Issues by Subsidiary-->
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  <!--Effective Income Tax Rate Reconciliation, Nondeductible Expense, Excess Compensation, Amount-->
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  <link:footnoteLink xlink:role="http://www.xbrl.org/2003/role/link" xlink:type="extended">
    <link:footnote xlink:label="Footnote-Item-1" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">Included in short-term investments on our consolidated balance sheet.</link:footnote>
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    <link:footnote xlink:label="Footnote-Item-2" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">$11.9 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</link:footnote>
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    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-3_lbl" xlink:to="Footnote-Item-2" xlink:type="arc" />
    <link:footnote xlink:label="Footnote-Item-3" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">$3.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</link:footnote>
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    <link:footnote xlink:label="Footnote-Item-4" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">$50.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</link:footnote>
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    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-6_lbl" xlink:to="Footnote-Item-4" xlink:type="arc" />
    <link:footnote xlink:label="Footnote-Item-5" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">$14.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</link:footnote>
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    <link:footnote xlink:label="Footnote-Item-6" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">We recognize our equity securities at 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 on our consolidated balance sheet.</link:footnote>
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    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-9_lbl" xlink:to="Footnote-Item-6" xlink:type="arc" />
    <link:footnote xlink:label="Footnote-Item-7" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">Includes investments classified as cash equivalents on our consolidated balance sheet.</link:footnote>
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    <link:footnote xlink:label="Footnote-Item-8" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">We hold our available-for-sale securities at amortized cost.</link:footnote>
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    <link:footnote xlink:label="Footnote-Item-9" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">Included in cash and cash equivalents on our consolidated balance sheet.</link:footnote>
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    <link:footnote xlink:label="Footnote-Item-10" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">We computed net income (loss) per share independently for each of the quarters presented. Therefore, the sum of the quarterly net income (loss) per share will not necessarily equal the total for the year.</link:footnote>
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    <link:footnote xlink:label="Footnote-Item-11" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income (loss) per share calculation for each of the quarters in 2018 and for the third and fourth quarters of 2017 considered our net income for Ionis on a stand-alone basis plus our share of Akcea's net loss for the period. To calculate the portion of Akcea's net loss attributable to our ownership, we multiplied Akcea's loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.</link:footnote>
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    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-40_lbl" xlink:to="Footnote-Item-11" xlink:type="arc" />
    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-41_lbl" xlink:to="Footnote-Item-11" xlink:type="arc" />
    <link:footnote xlink:label="Footnote-Item-12" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">Prior to Akcea's IPO in July 2017, we owned Akcea series A convertible preferred stock, which included a six percent cumulative dividend. Upon completion of Akcea's IPO in July 2017, our preferred stock was converted into common stock on a 1:1 basis. The preferred stock dividend was not paid at the IPO because the IPO was not a liquidation event or a change in control. During the three months ended September 30, 2017, Akcea used a two-class method to compute its net income (loss) per share because it had both common and preferred shares outstanding during the periods. The two-class method required Akcea to calculate its net income (loss) per share for each class of stock by dividing total distributable losses applicable to preferred and common stock, including the six percent cumulative dividend contractually due to series A convertible preferred shareholders, by the weighted-average of preferred and common shares outstanding during the requisite period. Since Akcea used the two-class method, accounting rules required us to include our portion of Akcea's net income (loss) per share for both Akcea's common and preferred shares that we owned in our calculation of basic and diluted net income (loss) per share for the three months ended September 30, 2017.</link:footnote>
    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-41_lbl" xlink:to="Footnote-Item-12" xlink:type="arc" />
    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-48_lbl" xlink:to="Footnote-Item-12" xlink:type="arc" />
    <link:footnote xlink:label="Footnote-Item-13" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">For the three months ended March 31, 2017, the calculation excluded the 1 percent and 2.75 percent notes because the effect on diluted earnings per share was anti-dilutive.</link:footnote>
    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-47_lbl" xlink:to="Footnote-Item-13" xlink:type="arc" />
    <link:footnote xlink:label="Footnote-Item-14" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">For the three months ended March 31, 2017, we owned 100 percent of Akcea. As a result, we did not have to adjust our earnings per share calculation. For the three months ended March 31, 2017, we had net income. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods.</link:footnote>
    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-47_lbl" xlink:to="Footnote-Item-14" xlink:type="arc" />
    <link:footnote xlink:label="Footnote-Item-15" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">For the three months ended December 31, 2018, we had net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods.</link:footnote>
    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-49_lbl" xlink:to="Footnote-Item-15" xlink:type="arc" />
    <link:footnote xlink:label="Footnote-Item-16" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">Included in other current assets on our consolidated balance sheet.</link:footnote>
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    <link:footnoteArc order="1.0" xlink:arcrole="http://www.xbrl.org/2003/arcrole/fact-footnote" xlink:from="Item-50_lbl" xlink:to="Footnote-Item-16" xlink:type="arc" />
    <link:footnote xlink:label="Footnote-Item-17" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">A tax benefit of $0.3 million was included in other comprehensive loss for the year ended December 31, 2018. There was no tax benefit or expense for other comprehensive loss for the years ended December 31, 2017 or 2016.</link:footnote>
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    <link:footnote xlink:label="Footnote-Item-18" xlink:role="http://www.xbrl.org/2003/role/footnote" xlink:type="resource" xml:lang="en-US">Our $12.5 million fixed rate note with Morgan Stanley is included in our current portion of long-term obligations on our consolidated balance sheet at December 31, 2018.</link:footnote>
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        <link:usedOn>link:calculationLink</link:usedOn>
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      <link:roleType roleURI="http://isispharm.com/role/SegmentInformationAndConcentrationOfBusinessRisk" id="SegmentInformationAndConcentrationOfBusinessRisk">
        <link:definition>060700 - Disclosure - Segment Information and Concentration of Business Risk</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
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      <link:roleType roleURI="http://isispharm.com/role/EmploymentBenefits" id="EmploymentBenefits">
        <link:definition>060800 - Disclosure - Employment Benefits</link:definition>
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        <link:usedOn>link:calculationLink</link:usedOn>
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      <link:roleType roleURI="http://isispharm.com/role/LegalProceedings" id="LegalProceedings">
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        <link:usedOn>link:calculationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
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        <link:definition>070100 - Disclosure - Organization and Significant Accounting Policies (Policies)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
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        <link:definition>080100 - Disclosure - Organization and Significant Accounting Policies (Tables)</link:definition>
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        <link:usedOn>link:calculationLink</link:usedOn>
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        <link:definition>080200 - Disclosure - Investments (Tables)</link:definition>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:calculationLink</link:usedOn>
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        <link:usedOn>link:calculationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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      <link:roleType roleURI="http://isispharm.com/role/SegmentInformationAndConcentrationOfBusinessRiskTables" id="SegmentInformationAndConcentrationOfBusinessRiskTables">
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        <link:definition>080700 - Disclosure - Segment Information and Concentration of Business Risk (Tables)</link:definition>
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        <link:usedOn>link:calculationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
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        <link:usedOn>link:definitionLink</link:usedOn>
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        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
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</xs:schema>
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<DESCRIPTION>XBRL TAXONOMY EXTENSION CALCULATION LINKBASE
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<DOCUMENT>
<TYPE>EX-101.LAB
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<DESCRIPTION>XBRL TAXONOMY EXTENSION LABEL LINKBASE
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    <link:label xlink:type="resource" xlink:label="us-gaap_AmortizationOfDebtDiscountPremium_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AmortizationOfDebtDiscountPremium_lbl" xml:lang="en-US" id="us-gaap_AmortizationOfDebtDiscountPremium_lbl">Amortization of convertible senior notes discount</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_AmortizationOfDebtDiscountPremium_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AmortizationOfDebtDiscountPremium_lbl1" xml:lang="en-US" id="us-gaap_AmortizationOfDebtDiscountPremium_lbl1">Amortization of Debt Discount (Premium)</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_AmortizationOfFinancingCostsAndDiscounts_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AmortizationOfFinancingCostsAndDiscounts_lbl1" xml:lang="en-US" id="us-gaap_AmortizationOfFinancingCostsAndDiscounts_lbl1">Amortization of Debt Issuance Costs and Discounts</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AmortizationOfFinancingCostsAndDiscounts" xlink:to="us-gaap_AmortizationOfFinancingCostsAndDiscounts_lbl1" xlink:title="label: AmortizationOfFinancingCostsAndDiscounts to us-gaap_AmortizationOfFinancingCostsAndDiscounts_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AmortizationOfFinancingCosts" xlink:to="us-gaap_AmortizationOfFinancingCosts_lbl1" xlink:title="label: AmortizationOfFinancingCosts to us-gaap_AmortizationOfFinancingCosts_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AmortizationOfLeasedAsset" xlink:label="AmortizationOfLeasedAsset" xlink:title="AmortizationOfLeasedAsset" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AmortizationOfLeasedAsset_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AmortizationOfLeasedAsset_lbl" xml:lang="en-US" id="us-gaap_AmortizationOfLeasedAsset_lbl">Amortization of long-term financing liability for leased facility</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_AmortizationOfLeasedAsset_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AmortizationOfLeasedAsset_lbl1" xml:lang="en-US" id="us-gaap_AmortizationOfLeasedAsset_lbl1">Amortization of Leased Asset</link:label>
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AmortizationOfIntangibleAssets" xlink:label="AmortizationOfIntangibleAssets" xlink:title="AmortizationOfIntangibleAssets" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AmortizationOfIntangibleAssets_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AmortizationOfIntangibleAssets_lbl" xml:lang="en-US" id="us-gaap_AmortizationOfIntangibleAssets_lbl">Amortization of patents</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_AmortizationOfIntangibleAssets_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AmortizationOfIntangibleAssets_lbl1" xml:lang="en-US" id="us-gaap_AmortizationOfIntangibleAssets_lbl1">Amortization of Intangible Assets</link:label>
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AssetImpairmentCharges" xlink:label="AssetImpairmentCharges" xlink:title="AssetImpairmentCharges" />
    <link:label xlink:type="resource" xlink:label="us-gaap_AssetImpairmentCharges_lbl" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_AssetImpairmentCharges_lbl" xml:lang="en-US" id="us-gaap_AssetImpairmentCharges_lbl">Charges related to write-down of long-lived assets</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_AssetImpairmentCharges_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AssetImpairmentCharges_lbl1" xml:lang="en-US" id="us-gaap_AssetImpairmentCharges_lbl1">Asset Impairment Charges</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_AssetImpairmentChargesAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_AssetImpairmentChargesAbstract_lbl" xml:lang="en-US" id="us-gaap_AssetImpairmentChargesAbstract_lbl">Long-Lived Assets [Abstract]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_AssetImpairmentChargesAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AssetImpairmentChargesAbstract_lbl1" xml:lang="en-US" id="us-gaap_AssetImpairmentChargesAbstract_lbl1">Asset Impairment Charges [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AssetImpairmentChargesAbstract" xlink:to="us-gaap_AssetImpairmentChargesAbstract_lbl1" xlink:title="label: AssetImpairmentChargesAbstract to us-gaap_AssetImpairmentChargesAbstract_lbl1" />
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    <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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AssetsAbstract" xlink:to="us-gaap_AssetsAbstract_lbl" xlink:title="label: AssetsAbstract to us-gaap_AssetsAbstract_lbl" />
    <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>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AssetsAbstract" xlink:to="us-gaap_AssetsAbstract_lbl1" xlink:title="label: AssetsAbstract to us-gaap_AssetsAbstract_lbl1" />
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    <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:label xlink:type="resource" xlink:label="us-gaap_AssetsFairValueDisclosure_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_AssetsFairValueDisclosure_lbl1" xml:lang="en-US" id="us-gaap_AssetsFairValueDisclosure_lbl1">Assets, Fair Value Disclosure</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AssetsFairValueDisclosure" xlink:to="us-gaap_AssetsFairValueDisclosure_lbl1" xlink:title="label: AssetsFairValueDisclosure to us-gaap_AssetsFairValueDisclosure_lbl1" />
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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">Total assets as of current period</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_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>
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionFairValue" xlink:label="AvailableForSaleSecuritiesContinuousUnrealizedLossPositionFairValue" xlink:title="AvailableForSaleSecuritiesContinuousUnrealizedLossPositionFairValue" />
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_AvailableForSaleSecuritiesDebtSecurities" xlink:label="AvailableForSaleSecuritiesDebtSecurities" xlink:title="AvailableForSaleSecuritiesDebtSecurities" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CashAndCashEquivalentsPeriodIncreaseDecrease" xlink:to="us-gaap_CashAndCashEquivalentsPeriodIncreaseDecrease_lbl1" xlink:title="label: CashAndCashEquivalentsPeriodIncreaseDecrease to us-gaap_CashAndCashEquivalentsPeriodIncreaseDecrease_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_CashAndCashEquivalentsAtCarryingValue_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_CashAndCashEquivalentsAtCarryingValue_lbl" xml:lang="en-US" id="us-gaap_CashAndCashEquivalentsAtCarryingValue_lbl">Cash and cash equivalents</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_CashAndCashEquivalentsAtCarryingValue_lbl2" xlink:role="http://www.xbrl.org/2003/role/periodStartLabel" xlink:title="us-gaap_CashAndCashEquivalentsAtCarryingValue_lbl2" xml:lang="en-US" id="us-gaap_CashAndCashEquivalentsAtCarryingValue_lbl2">Cash and cash equivalents at beginning of year</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CashAndCashEquivalentsAtCarryingValue" xlink:to="us-gaap_CashAndCashEquivalentsAtCarryingValue_lbl3" xlink:title="label: CashAndCashEquivalentsAtCarryingValue to us-gaap_CashAndCashEquivalentsAtCarryingValue_lbl3" />
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_ContractWithCustomerLiability" xlink:label="ContractWithCustomerLiability" xlink:title="ContractWithCustomerLiability" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_CurrentStateAndLocalTaxExpenseBenefit_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CurrentStateAndLocalTaxExpenseBenefit_lbl1" xml:lang="en-US" id="us-gaap_CurrentStateAndLocalTaxExpenseBenefit_lbl1">Current State and Local Tax Expense (Benefit)</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_CurrentIncomeTaxExpenseBenefit_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_CurrentIncomeTaxExpenseBenefit_lbl" xml:lang="en-US" id="us-gaap_CurrentIncomeTaxExpenseBenefit_lbl">Total current income tax (benefit) expense</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_CurrentIncomeTaxExpenseBenefit_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CurrentIncomeTaxExpenseBenefit_lbl1" xml:lang="en-US" id="us-gaap_CurrentIncomeTaxExpenseBenefit_lbl1">Current Income Tax Expense (Benefit)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CurrentIncomeTaxExpenseBenefit" xlink:to="us-gaap_CurrentIncomeTaxExpenseBenefit_lbl1" xlink:title="label: CurrentIncomeTaxExpenseBenefit to us-gaap_CurrentIncomeTaxExpenseBenefit_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CurrentForeignTaxExpenseBenefit" xlink:label="CurrentForeignTaxExpenseBenefit" xlink:title="CurrentForeignTaxExpenseBenefit" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CurrentForeignTaxExpenseBenefit_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CurrentForeignTaxExpenseBenefit_lbl" xml:lang="en-US" id="us-gaap_CurrentForeignTaxExpenseBenefit_lbl">Foreign</link:label>
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract" xlink:label="CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract" xlink:title="CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract_lbl" xml:lang="en-US" id="us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract_lbl">Current [Abstract]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract_lbl1" xml:lang="en-US" id="us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract_lbl1">Current Income Tax Expense (Benefit), Continuing Operations [Abstract]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_CurrentFederalTaxExpenseBenefit_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_CurrentFederalTaxExpenseBenefit_lbl" xml:lang="en-US" id="us-gaap_CurrentFederalTaxExpenseBenefit_lbl">Federal</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_CurrentFederalTaxExpenseBenefit_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CurrentFederalTaxExpenseBenefit_lbl1" xml:lang="en-US" id="us-gaap_CurrentFederalTaxExpenseBenefit_lbl1">Current Federal Tax Expense (Benefit)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CurrentFederalTaxExpenseBenefit" xlink:to="us-gaap_CurrentFederalTaxExpenseBenefit_lbl1" xlink:title="label: CurrentFederalTaxExpenseBenefit to us-gaap_CurrentFederalTaxExpenseBenefit_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_CustomerConcentrationRiskMember" xlink:label="CustomerConcentrationRiskMember" xlink:title="CustomerConcentrationRiskMember" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_CustomerConcentrationRiskMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_CustomerConcentrationRiskMember_lbl1" xml:lang="en-US" id="us-gaap_CustomerConcentrationRiskMember_lbl1">Customer Concentration Risk [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CustomerConcentrationRiskMember" xlink:to="us-gaap_CustomerConcentrationRiskMember_lbl1" xlink:title="label: CustomerConcentrationRiskMember to us-gaap_CustomerConcentrationRiskMember_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentMeasurementInput_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_DebtInstrumentMeasurementInput_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentMeasurementInput_lbl">Debt measurement input rate</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentMeasurementInput" xlink:to="us-gaap_DebtInstrumentMeasurementInput_lbl" xlink:title="label: DebtInstrumentMeasurementInput to us-gaap_DebtInstrumentMeasurementInput_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentMeasurementInput_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentMeasurementInput_lbl1" xml:lang="en-US" id="us-gaap_DebtInstrumentMeasurementInput_lbl1">Debt Instrument, Measurement Input</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentMeasurementInput" xlink:to="us-gaap_DebtInstrumentMeasurementInput_lbl1" xlink:title="label: DebtInstrumentMeasurementInput to us-gaap_DebtInstrumentMeasurementInput_lbl1" />
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    <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" />
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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>
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    <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" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments_lbl">Total shares of common stock subject to conversion (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertibleNumberOfEquityInstruments" xlink:to="us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments_lbl" xlink:title="label: DebtInstrumentConvertibleNumberOfEquityInstruments to us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments_lbl1" xml:lang="en-US" id="us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments_lbl1">Debt Instrument, Convertible, Number of Equity Instruments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertibleNumberOfEquityInstruments" xlink:to="us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments_lbl1" xlink:title="label: DebtInstrumentConvertibleNumberOfEquityInstruments to us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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/terseLabel" xlink:title="us-gaap_DebtInstrumentCarryingAmount_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentCarryingAmount_lbl">Principal amount of convertible notes outstanding</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentCarryingAmount_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentCarryingAmount_lbl1" xml:lang="en-US" id="us-gaap_DebtInstrumentCarryingAmount_lbl1">Long-term Debt, Gross</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_lbl1" xlink:title="label: DebtInstrumentCarryingAmount to us-gaap_DebtInstrumentCarryingAmount_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtPolicyTextBlock" xlink:label="DebtPolicyTextBlock" xlink:title="DebtPolicyTextBlock" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_DebtPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtPolicyTextBlock_lbl1" xml:lang="en-US" id="us-gaap_DebtPolicyTextBlock_lbl1">Debt, Policy [Policy Text Block]</link:label>
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    <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 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" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent_lbl">Carrying value of equity component</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent_lbl1" xml:lang="en-US" id="us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent_lbl1">Debt Instrument, Convertible, Carrying Amount of Equity Component</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent" xlink:to="us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent_lbl1" xlink:title="label: DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent to us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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/label" xlink:title="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl" xml:lang="en-US" id="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl">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_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/terseLabel" xlink:title="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl1" xml:lang="en-US" id="us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl1">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_lbl1" xlink:title="label: DebtInstrumentInterestRateStatedPercentage to us-gaap_DebtInstrumentInterestRateStatedPercentage_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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/label" 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:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_DebtInstrumentUnamortizedDiscount" xlink:label="DebtInstrumentUnamortizedDiscount" xlink:title="DebtInstrumentUnamortizedDiscount" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentUnamortizedDiscount" xlink:to="us-gaap_DebtInstrumentUnamortizedDiscount_lbl" xlink:title="label: DebtInstrumentUnamortizedDiscount to us-gaap_DebtInstrumentUnamortizedDiscount_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_DebtInstrumentUnamortizedDiscount_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_DebtInstrumentUnamortizedDiscount_lbl1" xml:lang="en-US" id="us-gaap_DebtInstrumentUnamortizedDiscount_lbl1">Debt Instrument, Unamortized Discount</link:label>
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    <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="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentUnamortizedDiscountPremiumNet" xlink:to="us-gaap_DebtInstrumentUnamortizedDiscountPremiumNet_lbl1" xlink:title="label: DebtInstrumentUnamortizedDiscountPremiumNet to us-gaap_DebtInstrumentUnamortizedDiscountPremiumNet_lbl1" />
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisAssetGainLossIncludedInEarnings1" xlink:label="FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisAssetGainLossIncludedInEarnings1" xlink:title="FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisAssetGainLossIncludedInEarnings1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_FiniteLivedIntangibleAssetsGross_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_FiniteLivedIntangibleAssetsGross_lbl1" xml:lang="en-US" id="us-gaap_FiniteLivedIntangibleAssetsGross_lbl1">Finite-Lived Intangible Assets, Gross</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain_lbl" xml:lang="en-US" id="us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain_lbl">Finite-Lived Intangible Assets, Major Class Name [Domain]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis_lbl" xml:lang="en-US" id="us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis_lbl">Finite-Lived Intangible Assets by Major Class [Axis]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_FiniteLivedIntangibleAssetUsefulLife_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_FiniteLivedIntangibleAssetUsefulLife_lbl" xml:lang="en-US" id="us-gaap_FiniteLivedIntangibleAssetUsefulLife_lbl">Estimated useful life</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_FiniteLivedIntangibleAssetUsefulLife_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_FiniteLivedIntangibleAssetUsefulLife_lbl1" xml:lang="en-US" id="us-gaap_FiniteLivedIntangibleAssetUsefulLife_lbl1">Finite-Lived Intangible Asset, Useful Life</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour_lbl" xml:lang="en-US" id="us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour_lbl">2022</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis_lbl" xml:lang="en-US" id="us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis_lbl">Initial Application Period Cumulative Effect Transition [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InitialApplicationPeriodCumulativeEffectTransitionAxis" xlink:to="us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis_lbl" xlink:title="label: InitialApplicationPeriodCumulativeEffectTransitionAxis to us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_InitialApplicationPeriodCumulativeEffectTransitionDomain" xlink:label="InitialApplicationPeriodCumulativeEffectTransitionDomain" xlink:title="InitialApplicationPeriodCumulativeEffectTransitionDomain" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InitialApplicationPeriodCumulativeEffectTransitionDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InitialApplicationPeriodCumulativeEffectTransitionDomain_lbl" xml:lang="en-US" id="us-gaap_InitialApplicationPeriodCumulativeEffectTransitionDomain_lbl">Initial Application Period Cumulative Effect Transition [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InitialApplicationPeriodCumulativeEffectTransitionDomain" xlink:to="us-gaap_InitialApplicationPeriodCumulativeEffectTransitionDomain_lbl" xlink:title="label: InitialApplicationPeriodCumulativeEffectTransitionDomain to us-gaap_InitialApplicationPeriodCumulativeEffectTransitionDomain_lbl" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl" xml:lang="en-US" id="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl">Patent Expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IntangibleAssetsFiniteLivedPolicy" xlink:to="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl" xlink:title="label: IntangibleAssetsFiniteLivedPolicy to us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl1" xml:lang="en-US" id="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl1">Intangible Assets, Finite-Lived, Policy [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IntangibleAssetsFiniteLivedPolicy" xlink:to="us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl1" xlink:title="label: IntangibleAssetsFiniteLivedPolicy to us-gaap_IntangibleAssetsFiniteLivedPolicy_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_InterestPayableCurrentAndNoncurrent_lbl" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="us-gaap_InterestPayableCurrentAndNoncurrent_lbl" xml:lang="en-US" id="us-gaap_InterestPayableCurrentAndNoncurrent_lbl">Less: fixed and determinable interest</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestPayableCurrentAndNoncurrent" xlink:to="us-gaap_InterestPayableCurrentAndNoncurrent_lbl" xlink:title="label: InterestPayableCurrentAndNoncurrent to us-gaap_InterestPayableCurrentAndNoncurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InterestPayableCurrentAndNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InterestPayableCurrentAndNoncurrent_lbl1" xml:lang="en-US" id="us-gaap_InterestPayableCurrentAndNoncurrent_lbl1">Interest Payable</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestPayableCurrentAndNoncurrent" xlink:to="us-gaap_InterestPayableCurrentAndNoncurrent_lbl1" xlink:title="label: InterestPayableCurrentAndNoncurrent to us-gaap_InterestPayableCurrentAndNoncurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_InterestExpense" xlink:label="InterestExpense" xlink:title="InterestExpense" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpense" xlink:to="us-gaap_InterestExpense_lbl" xlink:title="label: InterestExpense to us-gaap_InterestExpense_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InterestExpense_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InterestExpense_lbl1" xml:lang="en-US" id="us-gaap_InterestExpense_lbl1">Interest Expense</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestExpense" xlink:to="us-gaap_InterestExpense_lbl1" xlink:title="label: InterestExpense to us-gaap_InterestExpense_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_InterestPaidNet_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InterestPaidNet_lbl" xml:lang="en-US" id="us-gaap_InterestPaidNet_lbl">Interest paid</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestPaidNet" xlink:to="us-gaap_InterestPaidNet_lbl" xlink:title="label: InterestPaidNet to us-gaap_InterestPaidNet_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InterestPaidNet_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InterestPaidNet_lbl1" xml:lang="en-US" id="us-gaap_InterestPaidNet_lbl1">Interest Paid, Excluding Capitalized Interest, Operating Activities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InterestPaidNet" xlink:to="us-gaap_InterestPaidNet_lbl1" xlink:title="label: InterestPaidNet to us-gaap_InterestPaidNet_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_InternalRevenueServiceIRSMember" xlink:label="InternalRevenueServiceIRSMember" xlink:title="InternalRevenueServiceIRSMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InternalRevenueServiceIRSMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InternalRevenueServiceIRSMember_lbl" xml:lang="en-US" id="us-gaap_InternalRevenueServiceIRSMember_lbl">Federal [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InternalRevenueServiceIRSMember" xlink:to="us-gaap_InternalRevenueServiceIRSMember_lbl" xlink:title="label: InternalRevenueServiceIRSMember to us-gaap_InternalRevenueServiceIRSMember_lbl" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryWriteDown_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_InventoryWriteDown_lbl" xml:lang="en-US" id="us-gaap_InventoryWriteDown_lbl">Inventory write-off</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryWriteDown" xlink:to="us-gaap_InventoryWriteDown_lbl" xlink:title="label: InventoryWriteDown to us-gaap_InventoryWriteDown_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_InventoryWriteDown_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_InventoryWriteDown_lbl1" xml:lang="en-US" id="us-gaap_InventoryWriteDown_lbl1">Inventory Write-down</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="InventoryWriteDown" xlink:to="us-gaap_InventoryWriteDown_lbl1" xlink:title="label: InventoryWriteDown to us-gaap_InventoryWriteDown_lbl1" />
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    <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="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LicenseMember" xlink:label="LicenseMember" xlink:title="LicenseMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LicenseMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LicenseMember_lbl" xml:lang="en-US" id="us-gaap_LicenseMember_lbl">License Fees [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LicenseMember" xlink:to="us-gaap_LicenseMember_lbl" xlink:title="label: LicenseMember to us-gaap_LicenseMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LicenseMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LicenseMember_lbl1" xml:lang="en-US" id="us-gaap_LicenseMember_lbl1">License [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LicenseMember" xlink:to="us-gaap_LicenseMember_lbl1" xlink:title="label: LicenseMember to us-gaap_LicenseMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LineOfCreditFacilityTable" xlink:label="LineOfCreditFacilityTable" xlink:title="LineOfCreditFacilityTable" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LineOfCreditFacilityTable_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LineOfCreditFacilityTable_lbl" xml:lang="en-US" id="us-gaap_LineOfCreditFacilityTable_lbl">Line of Credit Facility [Table]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LineOfCreditFacilityTable" xlink:to="us-gaap_LineOfCreditFacilityTable_lbl" xlink:title="label: LineOfCreditFacilityTable to us-gaap_LineOfCreditFacilityTable_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LineOfCreditFacilityLineItems" xlink:label="LineOfCreditFacilityLineItems" xlink:title="LineOfCreditFacilityLineItems" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LineOfCreditFacilityLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LineOfCreditFacilityLineItems_lbl" xml:lang="en-US" id="us-gaap_LineOfCreditFacilityLineItems_lbl">Line of Credit Facility [Line Items]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LineOfCreditFacilityLineItems" xlink:to="us-gaap_LineOfCreditFacilityLineItems_lbl" xlink:title="label: LineOfCreditFacilityLineItems to us-gaap_LineOfCreditFacilityLineItems_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LineOfCreditFacilityAxis" xlink:label="LineOfCreditFacilityAxis" xlink:title="LineOfCreditFacilityAxis" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LineOfCreditFacilityAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LineOfCreditFacilityAxis_lbl" xml:lang="en-US" id="us-gaap_LineOfCreditFacilityAxis_lbl">Lender Name [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LineOfCreditFacilityAxis" xlink:to="us-gaap_LineOfCreditFacilityAxis_lbl" xlink:title="label: LineOfCreditFacilityAxis to us-gaap_LineOfCreditFacilityAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LineOfCreditFacilityAbstract" xlink:label="LineOfCreditFacilityAbstract" xlink:title="LineOfCreditFacilityAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LineOfCreditFacilityAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LineOfCreditFacilityAbstract_lbl" xml:lang="en-US" id="us-gaap_LineOfCreditFacilityAbstract_lbl">Financing Arrangements [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LineOfCreditFacilityAbstract" xlink:to="us-gaap_LineOfCreditFacilityAbstract_lbl" xlink:title="label: LineOfCreditFacilityAbstract to us-gaap_LineOfCreditFacilityAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LineOfCreditFacilityAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LineOfCreditFacilityAbstract_lbl1" xml:lang="en-US" id="us-gaap_LineOfCreditFacilityAbstract_lbl1">Line of Credit Facility [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LineOfCreditFacilityAbstract" xlink:to="us-gaap_LineOfCreditFacilityAbstract_lbl1" xlink:title="label: LineOfCreditFacilityAbstract to us-gaap_LineOfCreditFacilityAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LineOfCreditFacilityUnusedCapacityCommitmentFeePercentage" xlink:label="LineOfCreditFacilityUnusedCapacityCommitmentFeePercentage" xlink:title="LineOfCreditFacilityUnusedCapacityCommitmentFeePercentage" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LineOfCreditFacilityUnusedCapacityCommitmentFeePercentage_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LineOfCreditFacilityUnusedCapacityCommitmentFeePercentage_lbl" xml:lang="en-US" id="us-gaap_LineOfCreditFacilityUnusedCapacityCommitmentFeePercentage_lbl">Commitment fee percentage on unused capacity</link:label>
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LineOfCredit" xlink:label="LineOfCredit" xlink:title="LineOfCredit" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LineOfCredit_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LineOfCredit_lbl" xml:lang="en-US" id="us-gaap_LineOfCredit_lbl">Outstanding borrowings</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LineOfCredit" xlink:to="us-gaap_LineOfCredit_lbl" xlink:title="label: LineOfCredit to us-gaap_LineOfCredit_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LineOfCreditFacilityMaximumBorrowingCapacity" xlink:label="LineOfCreditFacilityMaximumBorrowingCapacity" xlink:title="LineOfCreditFacilityMaximumBorrowingCapacity" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LineOfCreditFacilityMaximumBorrowingCapacity_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LineOfCreditFacilityMaximumBorrowingCapacity_lbl" xml:lang="en-US" id="us-gaap_LineOfCreditFacilityMaximumBorrowingCapacity_lbl">Maximum borrowing capacity</link:label>
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LineOfCreditFacilityLenderDomain" xlink:label="LineOfCreditFacilityLenderDomain" xlink:title="LineOfCreditFacilityLenderDomain" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LineOfCreditFacilityLenderDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LineOfCreditFacilityLenderDomain_lbl" xml:lang="en-US" id="us-gaap_LineOfCreditFacilityLenderDomain_lbl">Line of Credit Facility, Lender [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LineOfCreditFacilityLenderDomain" xlink:to="us-gaap_LineOfCreditFacilityLenderDomain_lbl" xlink:title="label: LineOfCreditFacilityLenderDomain to us-gaap_LineOfCreditFacilityLenderDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LongTermDebtFairValue" xlink:label="LongTermDebtFairValue" xlink:title="LongTermDebtFairValue" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LongTermDebtFairValue_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LongTermDebtFairValue_lbl" xml:lang="en-US" id="us-gaap_LongTermDebtFairValue_lbl">Fair value of outstanding notes</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermDebtFairValue" xlink:to="us-gaap_LongTermDebtFairValue_lbl" xlink:title="label: LongTermDebtFairValue to us-gaap_LongTermDebtFairValue_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent" xlink:label="LongTermDebtAndCapitalLeaseObligationsCurrent" xlink:title="LongTermDebtAndCapitalLeaseObligationsCurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent_lbl" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent_lbl" xml:lang="en-US" id="us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent_lbl">Less: current portion</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermDebtAndCapitalLeaseObligationsCurrent" xlink:to="us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent_lbl" xlink:title="label: LongTermDebtAndCapitalLeaseObligationsCurrent to us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent_lbl1" xml:lang="en-US" id="us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent_lbl1">Long-term Debt and Capital Lease Obligations, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermDebtAndCapitalLeaseObligationsCurrent" xlink:to="us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent_lbl1" xlink:title="label: LongTermDebtAndCapitalLeaseObligationsCurrent to us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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>
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    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_LossContingencyAbstract" xlink:label="LossContingencyAbstract" xlink:title="LossContingencyAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LossContingencyAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_LossContingencyAbstract_lbl" xml:lang="en-US" id="us-gaap_LossContingencyAbstract_lbl">Legal Proceedings [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LossContingencyAbstract" xlink:to="us-gaap_LossContingencyAbstract_lbl" xlink:title="label: LossContingencyAbstract to us-gaap_LossContingencyAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_LossContingencyAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LossContingencyAbstract_lbl1" xml:lang="en-US" id="us-gaap_LossContingencyAbstract_lbl1">Loss Contingency [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LossContingencyAbstract" xlink:to="us-gaap_LossContingencyAbstract_lbl1" xlink:title="label: LossContingencyAbstract to us-gaap_LossContingencyAbstract_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_LossContingenciesLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_LossContingenciesLineItems_lbl" xml:lang="en-US" id="us-gaap_LossContingenciesLineItems_lbl">Loss Contingencies [Line Items]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LossContingenciesLineItems" xlink:to="us-gaap_LossContingenciesLineItems_lbl" xlink:title="label: LossContingenciesLineItems to us-gaap_LossContingenciesLineItems_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LossContingenciesTable" xlink:to="us-gaap_LossContingenciesTable_lbl" xlink:title="label: LossContingenciesTable to us-gaap_LossContingenciesTable_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LossContingencyPendingClaimsNumber" xlink:to="us-gaap_LossContingencyPendingClaimsNumber_lbl1" xlink:title="label: LossContingencyPendingClaimsNumber to us-gaap_LossContingencyPendingClaimsNumber_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_ManufacturingFacilityMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ManufacturingFacilityMember_lbl" xml:lang="en-US" id="us-gaap_ManufacturingFacilityMember_lbl">Manufacturing Facility [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ManufacturingFacilityMember" xlink:to="us-gaap_ManufacturingFacilityMember_lbl" xlink:title="label: ManufacturingFacilityMember to us-gaap_ManufacturingFacilityMember_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract" xlink:label="MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract" xlink:title="MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract_lbl" xml:lang="en-US" id="us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract_lbl">Annual Debt and Other Obligation Maturities [Abstract]</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_MeasurementInputTypeDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_MeasurementInputTypeDomain_lbl" xml:lang="en-US" id="us-gaap_MeasurementInputTypeDomain_lbl">Measurement Input Type [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MeasurementInputTypeDomain" xlink:to="us-gaap_MeasurementInputTypeDomain_lbl" xlink:title="label: MeasurementInputTypeDomain to us-gaap_MeasurementInputTypeDomain_lbl" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MeasurementInputTypeAxis" xlink:to="us-gaap_MeasurementInputTypeAxis_lbl" xlink:title="label: MeasurementInputTypeAxis to us-gaap_MeasurementInputTypeAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_MeasurementInputDiscountRateMember" xlink:label="MeasurementInputDiscountRateMember" xlink:title="MeasurementInputDiscountRateMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_MeasurementInputDiscountRateMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_MeasurementInputDiscountRateMember_lbl" xml:lang="en-US" id="us-gaap_MeasurementInputDiscountRateMember_lbl">Borrowing Rate [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MeasurementInputDiscountRateMember" xlink:to="us-gaap_MeasurementInputDiscountRateMember_lbl" xlink:title="label: MeasurementInputDiscountRateMember to us-gaap_MeasurementInputDiscountRateMember_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_MeasurementInputDiscountRateMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_MeasurementInputDiscountRateMember_lbl1" xml:lang="en-US" id="us-gaap_MeasurementInputDiscountRateMember_lbl1">Measurement Input, Discount Rate [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MeasurementInputDiscountRateMember" xlink:to="us-gaap_MeasurementInputDiscountRateMember_lbl1" xlink:title="label: MeasurementInputDiscountRateMember to us-gaap_MeasurementInputDiscountRateMember_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_MinorityInterest_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_MinorityInterest_lbl" xml:lang="en-US" id="us-gaap_MinorityInterest_lbl">Noncontrolling interest in Akcea Therapeutics, Inc.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MinorityInterest" xlink:to="us-gaap_MinorityInterest_lbl" xlink:title="label: MinorityInterest to us-gaap_MinorityInterest_lbl" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_MinorityInterestTable_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_MinorityInterestTable_lbl" xml:lang="en-US" id="us-gaap_MinorityInterestTable_lbl">Noncontrolling Interest [Table]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MinorityInterestTable" xlink:to="us-gaap_MinorityInterestTable_lbl" xlink:title="label: MinorityInterestTable to us-gaap_MinorityInterestTable_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_MinorityInterestLineItems" xlink:label="MinorityInterestLineItems" xlink:title="MinorityInterestLineItems" />
    <link:label xlink:type="resource" xlink:label="us-gaap_MinorityInterestLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_MinorityInterestLineItems_lbl" xml:lang="en-US" id="us-gaap_MinorityInterestLineItems_lbl">Noncontrolling Interest [Line Items]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MinorityInterestLineItems" xlink:to="us-gaap_MinorityInterestLineItems_lbl" xlink:title="label: MinorityInterestLineItems to us-gaap_MinorityInterestLineItems_lbl" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_MinorityInterestOwnershipPercentageByParent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_MinorityInterestOwnershipPercentageByParent_lbl" xml:lang="en-US" id="us-gaap_MinorityInterestOwnershipPercentageByParent_lbl">Percentage ownership</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MinorityInterestOwnershipPercentageByParent" xlink:to="us-gaap_MinorityInterestOwnershipPercentageByParent_lbl" xlink:title="label: MinorityInterestOwnershipPercentageByParent to us-gaap_MinorityInterestOwnershipPercentageByParent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_MinorityInterestOwnershipPercentageByParent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_MinorityInterestOwnershipPercentageByParent_lbl1" xml:lang="en-US" id="us-gaap_MinorityInterestOwnershipPercentageByParent_lbl1">Noncontrolling Interest, Ownership Percentage by Parent</link:label>
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    <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>
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    <link:label xlink:type="resource" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl1" xml:lang="en-US" id="us-gaap_NetCashProvidedByUsedInFinancingActivities_lbl1">Net Cash Provided by (Used in) Financing Activities</link:label>
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    <link:label xlink:type="resource" xlink:label="us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted_lbl1" xml:lang="en-US" id="us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted_lbl1">Net Income (Loss) Available to Common Stockholders, Diluted</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NoncontrollingInterestAbstract" xlink:to="us-gaap_NoncontrollingInterestAbstract_lbl" xlink:title="label: NoncontrollingInterestAbstract to us-gaap_NoncontrollingInterestAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_NoncontrollingInterestAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_NoncontrollingInterestAbstract_lbl1" xml:lang="en-US" id="us-gaap_NoncontrollingInterestAbstract_lbl1">Noncontrolling Interest [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NoncontrollingInterestAbstract" xlink:to="us-gaap_NoncontrollingInterestAbstract_lbl1" xlink:title="label: NoncontrollingInterestAbstract to us-gaap_NoncontrollingInterestAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLeasedAssetsLineItems" xlink:label="OperatingLeasedAssetsLineItems" xlink:title="OperatingLeasedAssetsLineItems" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasedAssetsLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeasedAssetsLineItems_lbl" xml:lang="en-US" id="us-gaap_OperatingLeasedAssetsLineItems_lbl">Operating Leased Assets [Line Items]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasedAssetsLineItems" xlink:to="us-gaap_OperatingLeasedAssetsLineItems_lbl" xlink:title="label: OperatingLeasedAssetsLineItems to us-gaap_OperatingLeasedAssetsLineItems_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent" xlink:label="OperatingLeasesFutureMinimumPaymentsDueCurrent" xlink:title="OperatingLeasesFutureMinimumPaymentsDueCurrent" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent_lbl" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent_lbl">2019</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsDueCurrent" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent_lbl" xlink:title="label: OperatingLeasesFutureMinimumPaymentsDueCurrent to us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent_lbl1" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent_lbl1">Operating Leases, Future Minimum Payments Due, Next Twelve Months</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsDueCurrent" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent_lbl1" xlink:title="label: OperatingLeasesFutureMinimumPaymentsDueCurrent to us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLeasesFutureMinimumPaymentsDue" xlink:label="OperatingLeasesFutureMinimumPaymentsDue" xlink:title="OperatingLeasesFutureMinimumPaymentsDue" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsDue_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsDue_lbl" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsDue_lbl">Total minimum payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsDue" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsDue_lbl" xlink:title="label: OperatingLeasesFutureMinimumPaymentsDue to us-gaap_OperatingLeasesFutureMinimumPaymentsDue_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsDue_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsDue_lbl1" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsDue_lbl1">Operating Leases, Future Minimum Payments Due</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsDue" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsDue_lbl1" xlink:title="label: OperatingLeasesFutureMinimumPaymentsDue to us-gaap_OperatingLeasesFutureMinimumPaymentsDue_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingSegmentsMember" xlink:label="OperatingSegmentsMember" xlink:title="OperatingSegmentsMember" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingSegmentsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingSegmentsMember_lbl" xml:lang="en-US" id="us-gaap_OperatingSegmentsMember_lbl">Operating Segments [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingSegmentsMember" xlink:to="us-gaap_OperatingSegmentsMember_lbl" xlink:title="label: OperatingSegmentsMember to us-gaap_OperatingSegmentsMember_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.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">Income (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/verboseLabel" xlink:title="us-gaap_OperatingIncomeLoss_lbl1" xml:lang="en-US" id="us-gaap_OperatingIncomeLoss_lbl1">Income (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_lbl1" xlink:title="label: OperatingIncomeLoss to us-gaap_OperatingIncomeLoss_lbl1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingIncomeLoss_lbl2" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingIncomeLoss_lbl2" xml:lang="en-US" id="us-gaap_OperatingIncomeLoss_lbl2">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_lbl2" xlink:title="label: OperatingIncomeLoss to us-gaap_OperatingIncomeLoss_lbl2" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingExpensesAbstract" xlink:label="OperatingExpensesAbstract" xlink:title="OperatingExpensesAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingExpensesAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OperatingExpensesAbstract_lbl" xml:lang="en-US" id="us-gaap_OperatingExpensesAbstract_lbl">Expenses:</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingExpensesAbstract" xlink:to="us-gaap_OperatingExpensesAbstract_lbl" xlink:title="label: OperatingExpensesAbstract to us-gaap_OperatingExpensesAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingExpensesAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingExpensesAbstract_lbl1" xml:lang="en-US" id="us-gaap_OperatingExpensesAbstract_lbl1">Operating Expenses [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingExpensesAbstract" xlink:to="us-gaap_OperatingExpensesAbstract_lbl1" xlink:title="label: OperatingExpensesAbstract to us-gaap_OperatingExpensesAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingExpenses" xlink:label="OperatingExpenses" xlink:title="OperatingExpenses" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingExpenses_lbl" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_OperatingExpenses_lbl" xml:lang="en-US" id="us-gaap_OperatingExpenses_lbl">Total operating expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingExpenses" xlink:to="us-gaap_OperatingExpenses_lbl" xlink:title="label: OperatingExpenses to us-gaap_OperatingExpenses_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingExpenses_lbl1" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="us-gaap_OperatingExpenses_lbl1" xml:lang="en-US" id="us-gaap_OperatingExpenses_lbl1">Total operating expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingExpenses" xlink:to="us-gaap_OperatingExpenses_lbl1" xlink:title="label: OperatingExpenses to us-gaap_OperatingExpenses_lbl1" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingExpenses_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OperatingExpenses_lbl2" xml:lang="en-US" id="us-gaap_OperatingExpenses_lbl2">Operating expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingExpenses" xlink:to="us-gaap_OperatingExpenses_lbl2" xlink:title="label: OperatingExpenses to us-gaap_OperatingExpenses_lbl2" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingExpenses_lbl3" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingExpenses_lbl3" xml:lang="en-US" id="us-gaap_OperatingExpenses_lbl3">Operating Expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingExpenses" xlink:to="us-gaap_OperatingExpenses_lbl3" xlink:title="label: OperatingExpenses to us-gaap_OperatingExpenses_lbl3" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLossCarryforwardsLineItems" xlink:label="OperatingLossCarryforwardsLineItems" xlink:title="OperatingLossCarryforwardsLineItems" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLossCarryforwardsLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLossCarryforwardsLineItems_lbl" xml:lang="en-US" id="us-gaap_OperatingLossCarryforwardsLineItems_lbl">Operating Loss Carryforwards [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLossCarryforwardsLineItems" xlink:to="us-gaap_OperatingLossCarryforwardsLineItems_lbl" xlink:title="label: OperatingLossCarryforwardsLineItems to us-gaap_OperatingLossCarryforwardsLineItems_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract" xlink:label="OperatingLeasesFutureMinimumPaymentsReceivableAbstract" xlink:title="OperatingLeasesFutureMinimumPaymentsReceivableAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract_lbl" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract_lbl">Annual Future Minimum Payments Under Operating Leases [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsReceivableAbstract" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract_lbl" xlink:title="label: OperatingLeasesFutureMinimumPaymentsReceivableAbstract to us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract_lbl1" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract_lbl1">Operating Leases, Future Minimum Payments Receivable [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsReceivableAbstract" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract_lbl1" xlink:title="label: OperatingLeasesFutureMinimumPaymentsReceivableAbstract to us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLossCarryforwards" xlink:label="OperatingLossCarryforwards" xlink:title="OperatingLossCarryforwards" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLossCarryforwards_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OperatingLossCarryforwards_lbl" xml:lang="en-US" id="us-gaap_OperatingLossCarryforwards_lbl">Net operating loss carryforwards</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLossCarryforwards" xlink:to="us-gaap_OperatingLossCarryforwards_lbl" xlink:title="label: OperatingLossCarryforwards to us-gaap_OperatingLossCarryforwards_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLossCarryforwards_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLossCarryforwards_lbl1" xml:lang="en-US" id="us-gaap_OperatingLossCarryforwards_lbl1">Operating Loss Carryforwards</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLossCarryforwards" xlink:to="us-gaap_OperatingLossCarryforwards_lbl1" xlink:title="label: OperatingLossCarryforwards to us-gaap_OperatingLossCarryforwards_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears" xlink:label="OperatingLeasesFutureMinimumPaymentsDueInFourYears" xlink:title="OperatingLeasesFutureMinimumPaymentsDueInFourYears" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears_lbl" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears_lbl">2022</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsDueInFourYears" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears_lbl" xlink:title="label: OperatingLeasesFutureMinimumPaymentsDueInFourYears to us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears_lbl1" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears_lbl1">Operating Leases, Future Minimum Payments, Due in Four Years</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsDueInFourYears" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears_lbl1" xlink:title="label: OperatingLeasesFutureMinimumPaymentsDueInFourYears to us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter" xlink:label="OperatingLeasesFutureMinimumPaymentsDueThereafter" xlink:title="OperatingLeasesFutureMinimumPaymentsDueThereafter" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter_lbl" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter_lbl">Thereafter</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsDueThereafter" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter_lbl" xlink:title="label: OperatingLeasesFutureMinimumPaymentsDueThereafter to us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter_lbl1" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter_lbl1">Operating Leases, Future Minimum Payments, Due Thereafter</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsDueThereafter" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter_lbl1" xlink:title="label: OperatingLeasesFutureMinimumPaymentsDueThereafter to us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears" xlink:label="OperatingLeasesFutureMinimumPaymentsDueInThreeYears" xlink:title="OperatingLeasesFutureMinimumPaymentsDueInThreeYears" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears_lbl" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears_lbl">2021</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsDueInThreeYears" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears_lbl" xlink:title="label: OperatingLeasesFutureMinimumPaymentsDueInThreeYears to us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears_lbl1" xml:lang="en-US" id="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears_lbl1">Operating Leases, Future Minimum Payments, Due in Three Years</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLeasesFutureMinimumPaymentsDueInThreeYears" xlink:to="us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears_lbl1" xlink:title="label: OperatingLeasesFutureMinimumPaymentsDueInThreeYears to us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears_lbl1" />
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    <link:label xlink:type="resource" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1_lbl1" xml:lang="en-US" id="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Options, Exercisable, Weighted Average Remaining Contractual Term</link:label>
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    <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" />
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    <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" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans" xlink:to="us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans_lbl1" xlink:title="label: StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans to us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans_lbl1" />
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    <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>
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    <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">Stock Issued During Period, Value, Share-based Compensation, Gross</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="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation" xlink:label="StockIssuedDuringPeriodSharesShareBasedCompensation" xlink:title="StockIssuedDuringPeriodSharesShareBasedCompensation" />
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    <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" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ValuationAllowancesAndReservesPeriodIncreaseDecrease" xlink:to="us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease_lbl" xlink:title="label: ValuationAllowancesAndReservesPeriodIncreaseDecrease to us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease_lbl1" xml:lang="en-US" id="us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease_lbl1">SEC Schedule, 12-09, Valuation Allowances and Reserves, Period Increase (Decrease)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ValuationAllowancesAndReservesPeriodIncreaseDecrease" xlink:to="us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease_lbl1" xlink:title="label: ValuationAllowancesAndReservesPeriodIncreaseDecrease to us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_VariableRateAxis" xlink:label="VariableRateAxis" xlink:title="VariableRateAxis" />
    <link:label xlink:type="resource" xlink:label="us-gaap_VariableRateAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_VariableRateAxis_lbl" xml:lang="en-US" id="us-gaap_VariableRateAxis_lbl">Variable Rate [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="VariableRateAxis" xlink:to="us-gaap_VariableRateAxis_lbl" xlink:title="label: VariableRateAxis to us-gaap_VariableRateAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_VariableRateDomain" xlink:label="VariableRateDomain" xlink:title="VariableRateDomain" />
    <link:label xlink:type="resource" xlink:label="us-gaap_VariableRateDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_VariableRateDomain_lbl" xml:lang="en-US" id="us-gaap_VariableRateDomain_lbl">Variable Rate [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="VariableRateDomain" xlink:to="us-gaap_VariableRateDomain_lbl" xlink:title="label: VariableRateDomain to us-gaap_VariableRateDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_WeightedAverageNumberOfSharesOutstandingBasic" xlink:label="WeightedAverageNumberOfSharesOutstandingBasic" xlink:title="WeightedAverageNumberOfSharesOutstandingBasic" />
    <link:label xlink:type="resource" xlink:label="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_lbl" xml:lang="en-US" id="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_lbl">Shares used in computing basic net income (loss) per share (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfSharesOutstandingBasic" xlink:to="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_lbl" xlink:title="label: WeightedAverageNumberOfSharesOutstandingBasic to us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_lbl1" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_lbl1" xml:lang="en-US" id="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_lbl1">Shares used in computing basic net income per share (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfSharesOutstandingBasic" xlink:to="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_lbl1" xlink:title="label: WeightedAverageNumberOfSharesOutstandingBasic to us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding" xlink:label="WeightedAverageNumberOfDilutedSharesOutstanding" xlink:title="WeightedAverageNumberOfDilutedSharesOutstanding" />
    <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 income (loss) per share (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfDilutedSharesOutstanding" xlink:to="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl" xlink:title="label: WeightedAverageNumberOfDilutedSharesOutstanding to us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl1" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl1" xml:lang="en-US" id="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl1">Shares used in computing diluted net income per share (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfDilutedSharesOutstanding" xlink:to="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl1" xlink:title="label: WeightedAverageNumberOfDilutedSharesOutstanding to us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract" xlink:label="WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract" xlink:title="WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract_lbl" xml:lang="en-US" id="us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract_lbl">Effect of Diluted Securities [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract" xlink:to="us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract_lbl" xlink:title="label: WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract to us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/us-gaap/2018/elts/us-gaap-2018-01-31.xsd#us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract" xlink:label="WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract" xlink:title="WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract" />
    <link:label xlink:type="resource" xlink:label="us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract_lbl" xml:lang="en-US" id="us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract_lbl">Shares (Denominator) [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract" xlink:to="us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract_lbl" xlink:title="label: WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract to us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract_lbl" />
    <link:label xlink:type="resource" xlink:label="us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract_lbl1" xml:lang="en-US" id="us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract_lbl1">Weighted Average Number of Shares Outstanding Reconciliation [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract" xlink:to="us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract_lbl1" xlink:title="label: WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract to us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_CounterpartyNameAxis" xlink:label="CounterpartyNameAxis" xlink:title="CounterpartyNameAxis" />
    <link:label xlink:type="resource" xlink:label="srt_CounterpartyNameAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_CounterpartyNameAxis_lbl" xml:lang="en-US" id="srt_CounterpartyNameAxis_lbl">Counterparty Name [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CounterpartyNameAxis" xlink:to="srt_CounterpartyNameAxis_lbl" xlink:title="label: CounterpartyNameAxis to srt_CounterpartyNameAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_ConsolidatedEntitiesAxis" xlink:label="ConsolidatedEntitiesAxis" xlink:title="ConsolidatedEntitiesAxis" />
    <link:label xlink:type="resource" xlink:label="srt_ConsolidatedEntitiesAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ConsolidatedEntitiesAxis_lbl" xml:lang="en-US" id="srt_ConsolidatedEntitiesAxis_lbl">Consolidated Entities [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidatedEntitiesAxis" xlink:to="srt_ConsolidatedEntitiesAxis_lbl" xlink:title="label: ConsolidatedEntitiesAxis to srt_ConsolidatedEntitiesAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_ConsolidatedEntitiesDomain" xlink:label="ConsolidatedEntitiesDomain" xlink:title="ConsolidatedEntitiesDomain" />
    <link:label xlink:type="resource" xlink:label="srt_ConsolidatedEntitiesDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ConsolidatedEntitiesDomain_lbl" xml:lang="en-US" id="srt_ConsolidatedEntitiesDomain_lbl">Consolidated Entities [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidatedEntitiesDomain" xlink:to="srt_ConsolidatedEntitiesDomain_lbl" xlink:title="label: ConsolidatedEntitiesDomain to srt_ConsolidatedEntitiesDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_ConsolidationItemsAxis" xlink:label="ConsolidationItemsAxis" xlink:title="ConsolidationItemsAxis" />
    <link:label xlink:type="resource" xlink:label="srt_ConsolidationItemsAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ConsolidationItemsAxis_lbl" xml:lang="en-US" id="srt_ConsolidationItemsAxis_lbl">Consolidation Items [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidationItemsAxis" xlink:to="srt_ConsolidationItemsAxis_lbl" xlink:title="label: ConsolidationItemsAxis to srt_ConsolidationItemsAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_ConsolidationItemsDomain" xlink:label="ConsolidationItemsDomain" xlink:title="ConsolidationItemsDomain" />
    <link:label xlink:type="resource" xlink:label="srt_ConsolidationItemsDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ConsolidationItemsDomain_lbl" xml:lang="en-US" id="srt_ConsolidationItemsDomain_lbl">Consolidation Items [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConsolidationItemsDomain" xlink:to="srt_ConsolidationItemsDomain_lbl" xlink:title="label: ConsolidationItemsDomain to srt_ConsolidationItemsDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_LitigationCaseAxis" xlink:label="LitigationCaseAxis" xlink:title="LitigationCaseAxis" />
    <link:label xlink:type="resource" xlink:label="srt_LitigationCaseAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_LitigationCaseAxis_lbl" xml:lang="en-US" id="srt_LitigationCaseAxis_lbl">Litigation Case [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LitigationCaseAxis" xlink:to="srt_LitigationCaseAxis_lbl" xlink:title="label: LitigationCaseAxis to srt_LitigationCaseAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_LitigationCaseTypeDomain" xlink:label="LitigationCaseTypeDomain" xlink:title="LitigationCaseTypeDomain" />
    <link:label xlink:type="resource" xlink:label="srt_LitigationCaseTypeDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_LitigationCaseTypeDomain_lbl" xml:lang="en-US" id="srt_LitigationCaseTypeDomain_lbl">Litigation Case [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LitigationCaseTypeDomain" xlink:to="srt_LitigationCaseTypeDomain_lbl" xlink:title="label: LitigationCaseTypeDomain to srt_LitigationCaseTypeDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MajorCustomersAxis" xlink:label="MajorCustomersAxis" xlink:title="MajorCustomersAxis" />
    <link:label xlink:type="resource" xlink:label="srt_MajorCustomersAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_MajorCustomersAxis_lbl" xml:lang="en-US" id="srt_MajorCustomersAxis_lbl">Customer [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MajorCustomersAxis" xlink:to="srt_MajorCustomersAxis_lbl" xlink:title="label: MajorCustomersAxis to srt_MajorCustomersAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MaximumMember" xlink:label="MaximumMember" xlink:title="MaximumMember" />
    <link:label xlink:type="resource" xlink:label="srt_MaximumMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="srt_MaximumMember_lbl" xml:lang="en-US" id="srt_MaximumMember_lbl">Maximum [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumMember" xlink:to="srt_MaximumMember_lbl" xlink:title="label: MaximumMember to srt_MaximumMember_lbl" />
    <link:label xlink:type="resource" xlink:label="srt_MaximumMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_MaximumMember_lbl1" xml:lang="en-US" id="srt_MaximumMember_lbl1">Maximum [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumMember" xlink:to="srt_MaximumMember_lbl1" xlink:title="label: MaximumMember to srt_MaximumMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_MinimumMember" xlink:label="MinimumMember" xlink:title="MinimumMember" />
    <link:label xlink:type="resource" xlink:label="srt_MinimumMember_lbl" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="srt_MinimumMember_lbl" xml:lang="en-US" id="srt_MinimumMember_lbl">Minimum [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MinimumMember" xlink:to="srt_MinimumMember_lbl" xlink:title="label: MinimumMember to srt_MinimumMember_lbl" />
    <link:label xlink:type="resource" xlink:label="srt_MinimumMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_MinimumMember_lbl1" xml:lang="en-US" id="srt_MinimumMember_lbl1">Minimum [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MinimumMember" xlink:to="srt_MinimumMember_lbl1" xlink:title="label: MinimumMember to srt_MinimumMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_NameOfMajorCustomerDomain" xlink:label="NameOfMajorCustomerDomain" xlink:title="NameOfMajorCustomerDomain" />
    <link:label xlink:type="resource" xlink:label="srt_NameOfMajorCustomerDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_NameOfMajorCustomerDomain_lbl" xml:lang="en-US" id="srt_NameOfMajorCustomerDomain_lbl">Customer [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NameOfMajorCustomerDomain" xlink:to="srt_NameOfMajorCustomerDomain_lbl" xlink:title="label: NameOfMajorCustomerDomain to srt_NameOfMajorCustomerDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_OwnershipDomain" xlink:label="OwnershipDomain" xlink:title="OwnershipDomain" />
    <link:label xlink:type="resource" xlink:label="srt_OwnershipDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_OwnershipDomain_lbl" xml:lang="en-US" id="srt_OwnershipDomain_lbl">Ownership [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OwnershipDomain" xlink:to="srt_OwnershipDomain_lbl" xlink:title="label: OwnershipDomain to srt_OwnershipDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_OwnershipAxis" xlink:label="OwnershipAxis" xlink:title="OwnershipAxis" />
    <link:label xlink:type="resource" xlink:label="srt_OwnershipAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_OwnershipAxis_lbl" xml:lang="en-US" id="srt_OwnershipAxis_lbl">Ownership [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OwnershipAxis" xlink:to="srt_OwnershipAxis_lbl" xlink:title="label: OwnershipAxis to srt_OwnershipAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_ProductsAndServicesDomain" xlink:label="ProductsAndServicesDomain" xlink:title="ProductsAndServicesDomain" />
    <link:label xlink:type="resource" xlink:label="srt_ProductsAndServicesDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ProductsAndServicesDomain_lbl" xml:lang="en-US" id="srt_ProductsAndServicesDomain_lbl">Products and Services [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProductsAndServicesDomain" xlink:to="srt_ProductsAndServicesDomain_lbl" xlink:title="label: ProductsAndServicesDomain to srt_ProductsAndServicesDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_ProductOrServiceAxis" xlink:label="ProductOrServiceAxis" xlink:title="ProductOrServiceAxis" />
    <link:label xlink:type="resource" xlink:label="srt_ProductOrServiceAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_ProductOrServiceAxis_lbl" xml:lang="en-US" id="srt_ProductOrServiceAxis_lbl">Products and Services [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ProductOrServiceAxis" xlink:to="srt_ProductOrServiceAxis_lbl" xlink:title="label: ProductOrServiceAxis to srt_ProductOrServiceAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeMember" xlink:label="RangeMember" xlink:title="RangeMember" />
    <link:label xlink:type="resource" xlink:label="srt_RangeMember_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_RangeMember_lbl" xml:lang="en-US" id="srt_RangeMember_lbl">Range [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RangeMember" xlink:to="srt_RangeMember_lbl" xlink:title="label: RangeMember to srt_RangeMember_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RangeAxis" xlink:label="RangeAxis" xlink:title="RangeAxis" />
    <link:label xlink:type="resource" xlink:label="srt_RangeAxis_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_RangeAxis_lbl" xml:lang="en-US" id="srt_RangeAxis_lbl">Range [Axis]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RangeAxis" xlink:to="srt_RangeAxis_lbl" xlink:title="label: RangeAxis to srt_RangeAxis_lbl" />
    <link:loc xlink:type="locator" xlink:href="http://xbrl.fasb.org/srt/2018/elts/srt-2018-01-31.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:label="RepurchaseAgreementCounterpartyNameDomain" xlink:title="RepurchaseAgreementCounterpartyNameDomain" />
    <link:label xlink:type="resource" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain_lbl" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="srt_RepurchaseAgreementCounterpartyNameDomain_lbl" xml:lang="en-US" id="srt_RepurchaseAgreementCounterpartyNameDomain_lbl">Counterparty Name [Domain]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RepurchaseAgreementCounterpartyNameDomain" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain_lbl" xlink:title="label: RepurchaseAgreementCounterpartyNameDomain to srt_RepurchaseAgreementCounterpartyNameDomain_lbl" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_OtherPartnersMember" xlink:label="OtherPartnersMember" xlink:title="OtherPartnersMember" />
    <link:label xlink:type="resource" xlink:label="ions_OtherPartnersMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_OtherPartnersMember_lbl" xml:lang="en-US" id="ions_OtherPartnersMember_lbl">Other collaboration partners, excluding Biogen Inc. (Biogen) and AstraZeneca PLC (AstraZeneca).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherPartnersMember" xlink:to="ions_OtherPartnersMember_lbl" xlink:title="label: OtherPartnersMember to ions_OtherPartnersMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_OtherPartnersMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_OtherPartnersMember_lbl1" xml:lang="en-US" id="ions_OtherPartnersMember_lbl1">Other Partners [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherPartnersMember" xlink:to="ions_OtherPartnersMember_lbl1" xlink:title="label: OtherPartnersMember to ions_OtherPartnersMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_OtherPartnersMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_OtherPartnersMember_lbl2" xml:lang="en-US" id="ions_OtherPartnersMember_lbl2">Other Partners [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OtherPartnersMember" xlink:to="ions_OtherPartnersMember_lbl2" xlink:title="label: OtherPartnersMember to ions_OtherPartnersMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AstraZenecaPLCMember" xlink:label="AstraZenecaPLCMember" xlink:title="AstraZenecaPLCMember" />
    <link:label xlink:type="resource" xlink:label="ions_AstraZenecaPLCMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AstraZenecaPLCMember_lbl" xml:lang="en-US" id="ions_AstraZenecaPLCMember_lbl">AstraZeneca PLC is a British-Swedish multinational pharmaceutical and biopharmaceutical company.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstraZenecaPLCMember" xlink:to="ions_AstraZenecaPLCMember_lbl" xlink:title="label: AstraZenecaPLCMember to ions_AstraZenecaPLCMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AstraZenecaPLCMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AstraZenecaPLCMember_lbl1" xml:lang="en-US" id="ions_AstraZenecaPLCMember_lbl1">AstraZeneca PLC [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstraZenecaPLCMember" xlink:to="ions_AstraZenecaPLCMember_lbl1" xlink:title="label: AstraZenecaPLCMember to ions_AstraZenecaPLCMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AstraZenecaPLCMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AstraZenecaPLCMember_lbl2" xml:lang="en-US" id="ions_AstraZenecaPLCMember_lbl2">AstraZeneca [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AstraZenecaPLCMember" xlink:to="ions_AstraZenecaPLCMember_lbl2" xlink:title="label: AstraZenecaPLCMember to ions_AstraZenecaPLCMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PeriodAfterBillingWhenPaymentIsReceived" xlink:label="PeriodAfterBillingWhenPaymentIsReceived" xlink:title="PeriodAfterBillingWhenPaymentIsReceived" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl" xml:lang="en-US" id="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl">The time period between billing a collaboration partner for goods delivered or services performed that are due unconditionally and payment is received from the collaboration partner, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterBillingWhenPaymentIsReceived" xlink:to="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl" xlink:title="label: PeriodAfterBillingWhenPaymentIsReceived to ions_PeriodAfterBillingWhenPaymentIsReceived_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl1" xml:lang="en-US" id="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl1">Period after billing when payment is received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterBillingWhenPaymentIsReceived" xlink:to="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl1" xlink:title="label: PeriodAfterBillingWhenPaymentIsReceived to ions_PeriodAfterBillingWhenPaymentIsReceived_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl2" xml:lang="en-US" id="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl2">Period of time after billing when payment is received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterBillingWhenPaymentIsReceived" xlink:to="ions_PeriodAfterBillingWhenPaymentIsReceived_lbl2" xlink:title="label: PeriodAfterBillingWhenPaymentIsReceived to ions_PeriodAfterBillingWhenPaymentIsReceived_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfAgreementsWithCollaborationPartner" xlink:label="NumberOfAgreementsWithCollaborationPartner" xlink:title="NumberOfAgreementsWithCollaborationPartner" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAgreementsWithCollaborationPartner_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfAgreementsWithCollaborationPartner_lbl" xml:lang="en-US" id="ions_NumberOfAgreementsWithCollaborationPartner_lbl">The number of agreements entered into with the collaboration partner.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAgreementsWithCollaborationPartner" xlink:to="ions_NumberOfAgreementsWithCollaborationPartner_lbl" xlink:title="label: NumberOfAgreementsWithCollaborationPartner to ions_NumberOfAgreementsWithCollaborationPartner_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAgreementsWithCollaborationPartner_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfAgreementsWithCollaborationPartner_lbl1" xml:lang="en-US" id="ions_NumberOfAgreementsWithCollaborationPartner_lbl1">Number of agreements with collaboration partner</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAgreementsWithCollaborationPartner" xlink:to="ions_NumberOfAgreementsWithCollaborationPartner_lbl1" xlink:title="label: NumberOfAgreementsWithCollaborationPartner to ions_NumberOfAgreementsWithCollaborationPartner_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAgreementsWithCollaborationPartner_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfAgreementsWithCollaborationPartner_lbl2" xml:lang="en-US" id="ions_NumberOfAgreementsWithCollaborationPartner_lbl2">Number of agreements</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAgreementsWithCollaborationPartner" xlink:to="ions_NumberOfAgreementsWithCollaborationPartner_lbl2" xlink:title="label: NumberOfAgreementsWithCollaborationPartner to ions_NumberOfAgreementsWithCollaborationPartner_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod" xlink:label="NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod" xlink:title="NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod" />
    <link:label xlink:type="resource" xlink:label="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl" xml:lang="en-US" id="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl">Amount of the effect of a change in accounting principle on revenue from the amortization of milestone payments achieved. The new revenue guidance requires the use of an input method to determine the amount amortized each reporting period rather than amortizing payments evenly over the period of obligation.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod" xlink:to="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl" xlink:title="label: NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod to ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl1" xml:lang="en-US" id="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl1">New Accounting Pronouncement or Change in Accounting Principle, Effect of Change on Revenue from amortization of payments using input method</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod" xlink:to="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl1" xlink:title="label: NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod to ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl2" xml:lang="en-US" id="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl2">Decrease in revenue from amortization of payments using input method under new revenue guidance</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod" xlink:to="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl2" xlink:title="label: NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod to ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance" xlink:label="NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance" xlink:title="NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance" />
    <link:label xlink:type="resource" xlink:label="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl" xml:lang="en-US" id="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl">Amount of the effect of a change in accounting principle on revenue from the amortization of milestone payments achieved. The new revenue guidance requires the amortization of more of the milestone payments achieved, rather than recognizing the milestone payments in full during the period achieved.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance" xlink:to="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl" xlink:title="label: NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance to ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl1" xml:lang="en-US" id="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl1">New Accounting Pronouncement or Change in Accounting Principle, Effect of Change on Revenue from amortization of milestone payments achieved under new revenue guidance</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance" xlink:to="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl1" xlink:title="label: NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance to ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl2" xml:lang="en-US" id="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl2">Increase in revenue from amortization of milestone payments achieved under new revenue guidance</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance" xlink:to="ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl2" xlink:title="label: NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance to ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_IONISHBVAndIONISHBVLMember" xlink:label="IONISHBVAndIONISHBVLMember" xlink:title="IONISHBVAndIONISHBVLMember" />
    <link:label xlink:type="resource" xlink:label="ions_IONISHBVAndIONISHBVLMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IONISHBVAndIONISHBVLMember_lbl" xml:lang="en-US" id="ions_IONISHBVAndIONISHBVLMember_lbl">IONIS-HBV and IONIS-HBV-L are two antisense drugs designed to reduce the production of viral proteins associated with hepatitis B virus, or HBV infection, a follow-on compound based on LICA technology.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISHBVAndIONISHBVLMember" xlink:to="ions_IONISHBVAndIONISHBVLMember_lbl" xlink:title="label: IONISHBVAndIONISHBVLMember to ions_IONISHBVAndIONISHBVLMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_IONISHBVAndIONISHBVLMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_IONISHBVAndIONISHBVLMember_lbl1" xml:lang="en-US" id="ions_IONISHBVAndIONISHBVLMember_lbl1">IONIS-HBV and IONIS-HBV-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISHBVAndIONISHBVLMember" xlink:to="ions_IONISHBVAndIONISHBVLMember_lbl1" xlink:title="label: IONISHBVAndIONISHBVLMember to ions_IONISHBVAndIONISHBVLMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfAntisenseDrugsInDevelopment" xlink:label="NumberOfAntisenseDrugsInDevelopment" xlink:title="NumberOfAntisenseDrugsInDevelopment" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAntisenseDrugsInDevelopment_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfAntisenseDrugsInDevelopment_lbl" xml:lang="en-US" id="ions_NumberOfAntisenseDrugsInDevelopment_lbl">The number of antisense drugs in development designed to reduce the production of viral proteins associated with hepatitis B virus, or HBV, infection under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAntisenseDrugsInDevelopment" xlink:to="ions_NumberOfAntisenseDrugsInDevelopment_lbl" xlink:title="label: NumberOfAntisenseDrugsInDevelopment to ions_NumberOfAntisenseDrugsInDevelopment_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAntisenseDrugsInDevelopment_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfAntisenseDrugsInDevelopment_lbl1" xml:lang="en-US" id="ions_NumberOfAntisenseDrugsInDevelopment_lbl1">Number of antisense drugs in development</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAntisenseDrugsInDevelopment" xlink:to="ions_NumberOfAntisenseDrugsInDevelopment_lbl1" xlink:title="label: NumberOfAntisenseDrugsInDevelopment to ions_NumberOfAntisenseDrugsInDevelopment_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PaymentReceivableUnderLicenseAgreement" xlink:label="PaymentReceivableUnderLicenseAgreement" xlink:title="PaymentReceivableUnderLicenseAgreement" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivableUnderLicenseAgreement_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentReceivableUnderLicenseAgreement_lbl" xml:lang="en-US" id="ions_PaymentReceivableUnderLicenseAgreement_lbl">The amount of payments expected to be received under the license agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivableUnderLicenseAgreement" xlink:to="ions_PaymentReceivableUnderLicenseAgreement_lbl" xlink:title="label: PaymentReceivableUnderLicenseAgreement to ions_PaymentReceivableUnderLicenseAgreement_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivableUnderLicenseAgreement_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentReceivableUnderLicenseAgreement_lbl1" xml:lang="en-US" id="ions_PaymentReceivableUnderLicenseAgreement_lbl1">Payment receivable under license agreement</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivableUnderLicenseAgreement" xlink:to="ions_PaymentReceivableUnderLicenseAgreement_lbl1" xlink:title="label: PaymentReceivableUnderLicenseAgreement to ions_PaymentReceivableUnderLicenseAgreement_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivableUnderLicenseAgreement_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PaymentReceivableUnderLicenseAgreement_lbl2" xml:lang="en-US" id="ions_PaymentReceivableUnderLicenseAgreement_lbl2">Payment receivable under license agreement</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivableUnderLicenseAgreement" xlink:to="ions_PaymentReceivableUnderLicenseAgreement_lbl2" xlink:title="label: PaymentReceivableUnderLicenseAgreement to ions_PaymentReceivableUnderLicenseAgreement_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_SublicenseRevenueMember" xlink:label="SublicenseRevenueMember" xlink:title="SublicenseRevenueMember" />
    <link:label xlink:type="resource" xlink:label="ions_SublicenseRevenueMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SublicenseRevenueMember_lbl" xml:lang="en-US" id="ions_SublicenseRevenueMember_lbl">Sublicense revenue received from Akcea Therapeutics, Inc. under their collaboration agreement with a strategic partner.</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SublicenseRevenueMember" xlink:to="ions_SublicenseRevenueMember_lbl2" xlink:title="label: SublicenseRevenueMember to ions_SublicenseRevenueMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PeriodBeforeCollaborationPartnerPaysRoyaltiesOnNetSalesOfProductAfterFirstCommercialSaleInBrazil" xlink:label="PeriodBeforeCollaborationPartnerPaysRoyaltiesOnNetSalesOfProductAfterFirstCommercialSaleInBrazil" xlink:title="PeriodBeforeCollaborationPartnerPaysRoyaltiesOnNetSalesOfProductAfterFirstCommercialSaleInBrazil" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner" xlink:label="RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner" xlink:title="RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner_lbl1" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner to ions_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner_lbl2" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner_lbl2">Royalty percentage received on net sales of each drug in Latin America from PTC</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner_lbl2" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner to ions_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties" xlink:label="RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties" xlink:title="RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl" xml:lang="en-US" id="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl">The minimum amount of revenue recognized in Latin America by the collaboration partner before paying royalties.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl1" xml:lang="en-US" id="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl1">Revenue recognized by collaboration partner in Latin America before paying royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties" xlink:to="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl1" xlink:title="label: RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties to ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl2" xml:lang="en-US" id="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl2">Minimum revenue recognized in Latin America by PTC before paying royalties</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties" xlink:to="ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl2" xlink:title="label: RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties to ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember_lbl">Represents information pertaining to the collaborative arrangement entered into with PTC Therapeutics by Akcea Therapeutics, Inc. in August 2018 to commercialize TEGSEDI and WAYLIVRA in Latin America.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in August 2018 with PTC Therapeutics [Member]</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval" xlink:label="PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval" xlink:title="PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl" xml:lang="en-US" id="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl">The amount of the payment receivable under the license agreement to be received on the earlier of approval by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval" xlink:to="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl" xlink:title="label: PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval to ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl1" xml:lang="en-US" id="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl1">Payment receivable under license agreement to be paid after approval</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval" xlink:to="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl1" xlink:title="label: PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval to ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl2" xml:lang="en-US" id="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl2">Payment to be received on earlier of FDA or EMA approval of WAYLIVRA</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval" xlink:to="ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl2" xlink:title="label: PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval to ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture" xlink:label="PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture" xlink:title="PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture" />
    <link:label xlink:type="resource" xlink:label="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture_lbl" xml:lang="en-US" id="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture_lbl">The potential premium received if common stock is purchased in the future under a Stock Purchase Agreement (SPA) in conjunction with the collaboration agreement.</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture" xlink:to="ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture_lbl2" xlink:title="label: PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture to ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PortionOfUpfrontPaymentRetained" xlink:label="PortionOfUpfrontPaymentRetained" xlink:title="PortionOfUpfrontPaymentRetained" />
    <link:label xlink:type="resource" xlink:label="ions_PortionOfUpfrontPaymentRetained_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PortionOfUpfrontPaymentRetained_lbl" xml:lang="en-US" id="ions_PortionOfUpfrontPaymentRetained_lbl">The amount of the upfront payment received during the period under the collaboration agreement that was retained by the entity.</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PortionOfUpfrontPaymentRetained" xlink:to="ions_PortionOfUpfrontPaymentRetained_lbl1" xlink:title="label: PortionOfUpfrontPaymentRetained to ions_PortionOfUpfrontPaymentRetained_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PortionOfUpfrontPaymentRetained_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PortionOfUpfrontPaymentRetained_lbl2" xml:lang="en-US" id="ions_PortionOfUpfrontPaymentRetained_lbl2">Portion of upfront payment retained</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PortionOfUpfrontPaymentRetained" xlink:to="ions_PortionOfUpfrontPaymentRetained_lbl2" xlink:title="label: PortionOfUpfrontPaymentRetained to ions_PortionOfUpfrontPaymentRetained_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PremiumReceivedOnSharesIssued" xlink:label="PremiumReceivedOnSharesIssued" xlink:title="PremiumReceivedOnSharesIssued" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumReceivedOnSharesIssued_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PremiumReceivedOnSharesIssued_lbl" xml:lang="en-US" id="ions_PremiumReceivedOnSharesIssued_lbl">The total amount of the premium received over the trading price of common stock at the time of purchase.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumReceivedOnSharesIssued" xlink:to="ions_PremiumReceivedOnSharesIssued_lbl" xlink:title="label: PremiumReceivedOnSharesIssued to ions_PremiumReceivedOnSharesIssued_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumReceivedOnSharesIssued_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PremiumReceivedOnSharesIssued_lbl1" xml:lang="en-US" id="ions_PremiumReceivedOnSharesIssued_lbl1">Premium received on shares issued</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumReceivedOnSharesIssued" xlink:to="ions_PremiumReceivedOnSharesIssued_lbl1" xlink:title="label: PremiumReceivedOnSharesIssued to ions_PremiumReceivedOnSharesIssued_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumReceivedOnSharesIssued_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PremiumReceivedOnSharesIssued_lbl2" xml:lang="en-US" id="ions_PremiumReceivedOnSharesIssued_lbl2">Premium received on shares issued</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumReceivedOnSharesIssued" xlink:to="ions_PremiumReceivedOnSharesIssued_lbl2" xlink:title="label: PremiumReceivedOnSharesIssued to ions_PremiumReceivedOnSharesIssued_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsReceivableForMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl">The maximum amount of payments receivable for milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForMilestones to ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl1">Maximum amount of payments receivable for milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForMilestones to ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl2">Maximum amount of payments receivable for milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForMilestones to ions_MaximumAmountOfPaymentsReceivableForMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_DeliveryOfAKCEAAPOALMember" xlink:label="DeliveryOfAKCEAAPOALMember" xlink:title="DeliveryOfAKCEAAPOALMember" />
    <link:label xlink:type="resource" xlink:label="ions_DeliveryOfAKCEAAPOALMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DeliveryOfAKCEAAPOALMember_lbl" xml:lang="en-US" id="ions_DeliveryOfAKCEAAPOALMember_lbl">Delivery of AKCEA-APO(a)-L, an antisense therapy with the potential to significantly reduce cardiovascular risk in patients suffering from high levels of the lipoprotein Lp(a).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeliveryOfAKCEAAPOALMember" xlink:to="ions_DeliveryOfAKCEAAPOALMember_lbl" xlink:title="label: DeliveryOfAKCEAAPOALMember to ions_DeliveryOfAKCEAAPOALMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_DeliveryOfAKCEAAPOALMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DeliveryOfAKCEAAPOALMember_lbl1" xml:lang="en-US" id="ions_DeliveryOfAKCEAAPOALMember_lbl1">Delivery of AKCEA-APO(a)-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeliveryOfAKCEAAPOALMember" xlink:to="ions_DeliveryOfAKCEAAPOALMember_lbl1" xlink:title="label: DeliveryOfAKCEAAPOALMember to ions_DeliveryOfAKCEAAPOALMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_DeliveryOfAKCEAAPOALMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_DeliveryOfAKCEAAPOALMember_lbl2" xml:lang="en-US" id="ions_DeliveryOfAKCEAAPOALMember_lbl2">Delivery of AKCEA-APO(a)-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeliveryOfAKCEAAPOALMember" xlink:to="ions_DeliveryOfAKCEAAPOALMember_lbl2" xlink:title="label: DeliveryOfAKCEAAPOALMember to ions_DeliveryOfAKCEAAPOALMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee" xlink:label="PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee" xlink:title="PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl" xml:lang="en-US" id="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl">The percentage of license fees, milestone payments and royalties paid as sublicense fee under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee" xlink:to="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl" xlink:title="label: PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee to ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl1" xml:lang="en-US" id="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl1">Percentage of license fees, milestone payments and royalties paid as sublicense fee</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee" xlink:to="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl1" xlink:title="label: PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee to ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl2" xml:lang="en-US" id="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl2">Percentage of license fees, milestone payments and royalties paid as sublicense fee</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee" xlink:to="ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl2" xlink:title="label: PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee to ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember" xlink:label="ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember" xlink:title="ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl">Research and development (R&amp;D) services for AKCEA-APOCIII-L, an antisense therapy with the potential to significantly reduce cardiovascular risk in patients suffering from high levels of the lipoprotein ApoCIII.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember" xlink:to="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl" xlink:title="label: ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember to ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl1" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl1">Research and Development Services for AKCEA-APOCIII-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember" xlink:to="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl1" xlink:title="label: ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember to ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl2" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl2">R&amp;D Services for AKCEA-APOCIII-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember" xlink:to="ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl2" xlink:title="label: ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember to ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_DeliveryOfAKCEAAPOCIIILMember" xlink:label="DeliveryOfAKCEAAPOCIIILMember" xlink:title="DeliveryOfAKCEAAPOCIIILMember" />
    <link:label xlink:type="resource" xlink:label="ions_DeliveryOfAKCEAAPOCIIILMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DeliveryOfAKCEAAPOCIIILMember_lbl" xml:lang="en-US" id="ions_DeliveryOfAKCEAAPOCIIILMember_lbl">Delivery of AKCEA-APOCIII-L, an antisense therapy with the potential to significantly reduce cardiovascular risk in patients suffering from high levels of the lipoprotein ApoCIII.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeliveryOfAKCEAAPOCIIILMember" xlink:to="ions_DeliveryOfAKCEAAPOCIIILMember_lbl" xlink:title="label: DeliveryOfAKCEAAPOCIIILMember to ions_DeliveryOfAKCEAAPOCIIILMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_DeliveryOfAKCEAAPOCIIILMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DeliveryOfAKCEAAPOCIIILMember_lbl1" xml:lang="en-US" id="ions_DeliveryOfAKCEAAPOCIIILMember_lbl1">Delivery of AKCEA-APOCIII-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeliveryOfAKCEAAPOCIIILMember" xlink:to="ions_DeliveryOfAKCEAAPOCIIILMember_lbl1" xlink:title="label: DeliveryOfAKCEAAPOCIIILMember to ions_DeliveryOfAKCEAAPOCIIILMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_DeliveryOfAKCEAAPOCIIILMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_DeliveryOfAKCEAAPOCIIILMember_lbl2" xml:lang="en-US" id="ions_DeliveryOfAKCEAAPOCIIILMember_lbl2">Delivery of AKCEA-APOCIII-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeliveryOfAKCEAAPOCIIILMember" xlink:to="ions_DeliveryOfAKCEAAPOCIIILMember_lbl2" xlink:title="label: DeliveryOfAKCEAAPOCIIILMember to ions_DeliveryOfAKCEAAPOCIIILMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AKCEAAPOCIIILMember" xlink:label="AKCEAAPOCIIILMember" xlink:title="AKCEAAPOCIIILMember" />
    <link:label xlink:type="resource" xlink:label="ions_AKCEAAPOCIIILMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AKCEAAPOCIIILMember_lbl" xml:lang="en-US" id="ions_AKCEAAPOCIIILMember_lbl">An antisense therapy with the potential to significantly reduce cardiovascular risk in patients suffering from high levels of the lipoprotein ApoCIII.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AKCEAAPOCIIILMember" xlink:to="ions_AKCEAAPOCIIILMember_lbl" xlink:title="label: AKCEAAPOCIIILMember to ions_AKCEAAPOCIIILMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AKCEAAPOCIIILMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AKCEAAPOCIIILMember_lbl1" xml:lang="en-US" id="ions_AKCEAAPOCIIILMember_lbl1">AKCEA-APOCIII-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AKCEAAPOCIIILMember" xlink:to="ions_AKCEAAPOCIIILMember_lbl1" xlink:title="label: AKCEAAPOCIIILMember to ions_AKCEAAPOCIIILMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AKCEAAPOCIIILMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AKCEAAPOCIIILMember_lbl2" xml:lang="en-US" id="ions_AKCEAAPOCIIILMember_lbl2">AKCEA-APOCIII-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AKCEAAPOCIIILMember" xlink:to="ions_AKCEAAPOCIIILMember_lbl2" xlink:title="label: AKCEAAPOCIIILMember to ions_AKCEAAPOCIIILMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PortionOfUpfrontPaymentPaidAsASublicenseFee" xlink:label="PortionOfUpfrontPaymentPaidAsASublicenseFee" xlink:title="PortionOfUpfrontPaymentPaidAsASublicenseFee" />
    <link:label xlink:type="resource" xlink:label="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl" xml:lang="en-US" id="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl">The amount of the upfront payment received during the period under the collaboration agreement that was paid as a sublicense fee.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PortionOfUpfrontPaymentPaidAsASublicenseFee" xlink:to="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl" xlink:title="label: PortionOfUpfrontPaymentPaidAsASublicenseFee to ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl1" xml:lang="en-US" id="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl1">Portion of upfront payment paid as a sublicense fee</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PortionOfUpfrontPaymentPaidAsASublicenseFee" xlink:to="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl1" xlink:title="label: PortionOfUpfrontPaymentPaidAsASublicenseFee to ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl2" xml:lang="en-US" id="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl2">Portion of upfront payment paid as a sublicense fee</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PortionOfUpfrontPaymentPaidAsASublicenseFee" xlink:to="ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl2" xlink:title="label: PortionOfUpfrontPaymentPaidAsASublicenseFee to ions_PortionOfUpfrontPaymentPaidAsASublicenseFee_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_RoyaltyPercentageReceivedOnSalesOfDrug" xlink:label="RoyaltyPercentageReceivedOnSalesOfDrug" xlink:title="RoyaltyPercentageReceivedOnSalesOfDrug" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl">Royalty percentage received on the sales of a drug by a collaboration partner under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnSalesOfDrug" xlink:to="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl" xlink:title="label: RoyaltyPercentageReceivedOnSalesOfDrug to ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl1" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl1">Royalty percentage received on sales of drug</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnSalesOfDrug" xlink:to="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl1" xlink:title="label: RoyaltyPercentageReceivedOnSalesOfDrug to ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl2" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl2">Royalty percentage received on sales of drug</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnSalesOfDrug" xlink:to="ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl2" xlink:title="label: RoyaltyPercentageReceivedOnSalesOfDrug to ions_RoyaltyPercentageReceivedOnSalesOfDrug_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LicenseFeePaidPerDrug" xlink:label="LicenseFeePaidPerDrug" xlink:title="LicenseFeePaidPerDrug" />
    <link:label xlink:type="resource" xlink:label="ions_LicenseFeePaidPerDrug_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LicenseFeePaidPerDrug_lbl" xml:lang="en-US" id="ions_LicenseFeePaidPerDrug_lbl">The license fee payment receivable per drug under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LicenseFeePaidPerDrug" xlink:to="ions_LicenseFeePaidPerDrug_lbl" xlink:title="label: LicenseFeePaidPerDrug to ions_LicenseFeePaidPerDrug_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LicenseFeePaidPerDrug_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LicenseFeePaidPerDrug_lbl1" xml:lang="en-US" id="ions_LicenseFeePaidPerDrug_lbl1">License fee receivable per drug</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LicenseFeePaidPerDrug" xlink:to="ions_LicenseFeePaidPerDrug_lbl1" xlink:title="label: LicenseFeePaidPerDrug to ions_LicenseFeePaidPerDrug_lbl1" />
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    <link:label xlink:type="resource" xlink:label="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl" xml:lang="en-US" id="ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid_lbl">The cash inflow from the sale of common stock, including the premium paid for the purchase of common stock.</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_IONISAZ525Member" xlink:label="IONISAZ525Member" xlink:title="IONISAZ525Member" />
    <link:label xlink:type="resource" xlink:label="ions_IONISAZ525Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IONISAZ525Member_lbl" xml:lang="en-US" id="ions_IONISAZ525Member_lbl">A drug designed to treat a genetically associated form of kidney disease.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_IONISAZ525Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_IONISAZ525Member_lbl1" xml:lang="en-US" id="ions_IONISAZ525Member_lbl1">IONIS-AZ5-2.5 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISAZ525Member" xlink:to="ions_IONISAZ525Member_lbl1" xlink:title="label: IONISAZ525Member to ions_IONISAZ525Member_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISAZ525Member" xlink:to="ions_IONISAZ525Member_lbl2" xlink:title="label: IONISAZ525Member to ions_IONISAZ525Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl">Represents information pertaining to the collaborative arrangement entered into with AstraZeneca PLC in July 2015 to discover and develop antisense therapies for treating cardiovascular and metabolic diseases primarily focused on targets in the kidney and renal diseases.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in July 2015 with AstraZeneca [Member]</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl2">Cardiac, Renal and Metabolic Diseases [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember_lbl">Represents information pertaining to the collaborative arrangement entered into with AstraZeneca PLC in December 2012 and amended in January 2016 to discover and develop antisense drugs for cancer.</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfObligationsFullySatisified" xlink:label="NumberOfObligationsFullySatisified" xlink:title="NumberOfObligationsFullySatisified" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfObligationsFullySatisified_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfObligationsFullySatisified_lbl" xml:lang="en-US" id="ions_NumberOfObligationsFullySatisified_lbl">The number of obligations fully satisfied under the collaboration agreement for which revenue is recognized over the period of performance.</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfObligationsFullySatisified" xlink:to="ions_NumberOfObligationsFullySatisified_lbl2" xlink:title="label: NumberOfObligationsFullySatisified to ions_NumberOfObligationsFullySatisified_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements" xlink:label="NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements" xlink:title="NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements_lbl" xml:lang="en-US" id="ions_NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements_lbl">The number of drugs that can be licensed by the partner(s) under their respective collaboration agreements.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements_lbl1" xml:lang="en-US" id="ions_NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements_lbl1">Number of drugs that can be licensed under option in collaboration agreements</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfProgramsAdvanced" xlink:label="NumberOfProgramsAdvanced" xlink:title="NumberOfProgramsAdvanced" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsAdvanced_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfProgramsAdvanced_lbl" xml:lang="en-US" id="ions_NumberOfProgramsAdvanced_lbl">The number of programs advanced under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsAdvanced" xlink:to="ions_NumberOfProgramsAdvanced_lbl" xlink:title="label: NumberOfProgramsAdvanced to ions_NumberOfProgramsAdvanced_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsAdvanced_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfProgramsAdvanced_lbl1" xml:lang="en-US" id="ions_NumberOfProgramsAdvanced_lbl1">Number of programs advanced</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsAdvanced" xlink:to="ions_NumberOfProgramsAdvanced_lbl1" xlink:title="label: NumberOfProgramsAdvanced to ions_NumberOfProgramsAdvanced_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsAdvanced_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfProgramsAdvanced_lbl2" xml:lang="en-US" id="ions_NumberOfProgramsAdvanced_lbl2">Number of programs advanced</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsAdvanced" xlink:to="ions_NumberOfProgramsAdvanced_lbl2" xlink:title="label: NumberOfProgramsAdvanced to ions_NumberOfProgramsAdvanced_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_IONISAZ625Member" xlink:label="IONISAZ625Member" xlink:title="IONISAZ625Member" />
    <link:label xlink:type="resource" xlink:label="ions_IONISAZ625Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IONISAZ625Member_lbl" xml:lang="en-US" id="ions_IONISAZ625Member_lbl">A drug designed to inhibit an undisclosed target to treat patients with nonalcoholic steatohepatitis, or NASH.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISAZ625Member" xlink:to="ions_IONISAZ625Member_lbl" xlink:title="label: IONISAZ625Member to ions_IONISAZ625Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_IONISAZ625Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_IONISAZ625Member_lbl1" xml:lang="en-US" id="ions_IONISAZ625Member_lbl1">IONIS-AZ6-2.5 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISAZ625Member" xlink:to="ions_IONISAZ625Member_lbl1" xlink:title="label: IONISAZ625Member to ions_IONISAZ625Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_IONISAZ625Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_IONISAZ625Member_lbl2" xml:lang="en-US" id="ions_IONISAZ625Member_lbl2">IONIS-AZ6-2.5 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISAZ625Member" xlink:to="ions_IONISAZ625Member_lbl2" xlink:title="label: IONISAZ625Member to ions_IONISAZ625Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_DanvatirsenMember" xlink:label="DanvatirsenMember" xlink:title="DanvatirsenMember" />
    <link:label xlink:type="resource" xlink:label="ions_DanvatirsenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DanvatirsenMember_lbl" xml:lang="en-US" id="ions_DanvatirsenMember_lbl">Danvatirsen (formerly IONIS-STAT3-2.5, also known as AZD9150) was designed to treat cancer by inhibiting the production of a gene critical for tumor cell growth and survival. Signal transducer and activator of transcription 3, or STAT3, is over-active in a variety of cancers, including brain, lung, breast, bone, liver and multiple myeloma and promotes tumor cell growth and prevents cell death.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DanvatirsenMember" xlink:to="ions_DanvatirsenMember_lbl" xlink:title="label: DanvatirsenMember to ions_DanvatirsenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_DanvatirsenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DanvatirsenMember_lbl1" xml:lang="en-US" id="ions_DanvatirsenMember_lbl1">Danvatirsen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DanvatirsenMember" xlink:to="ions_DanvatirsenMember_lbl1" xlink:title="label: DanvatirsenMember to ions_DanvatirsenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_DanvatirsenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_DanvatirsenMember_lbl2" xml:lang="en-US" id="ions_DanvatirsenMember_lbl2">Danvatirsen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DanvatirsenMember" xlink:to="ions_DanvatirsenMember_lbl2" xlink:title="label: DanvatirsenMember to ions_DanvatirsenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_UndisclosedProgramMember" xlink:label="UndisclosedProgramMember" xlink:title="UndisclosedProgramMember" />
    <link:label xlink:type="resource" xlink:label="ions_UndisclosedProgramMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_UndisclosedProgramMember_lbl" xml:lang="en-US" id="ions_UndisclosedProgramMember_lbl">An undisclosed program under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UndisclosedProgramMember" xlink:to="ions_UndisclosedProgramMember_lbl" xlink:title="label: UndisclosedProgramMember to ions_UndisclosedProgramMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_UndisclosedProgramMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_UndisclosedProgramMember_lbl1" xml:lang="en-US" id="ions_UndisclosedProgramMember_lbl1">Undisclosed Program [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UndisclosedProgramMember" xlink:to="ions_UndisclosedProgramMember_lbl1" xlink:title="label: UndisclosedProgramMember to ions_UndisclosedProgramMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_UndisclosedProgramMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_UndisclosedProgramMember_lbl2" xml:lang="en-US" id="ions_UndisclosedProgramMember_lbl2">Undisclosed Program [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UndisclosedProgramMember" xlink:to="ions_UndisclosedProgramMember_lbl2" xlink:title="label: UndisclosedProgramMember to ions_UndisclosedProgramMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_RevenueFromContractWithCustomerTransactionPriceAdditions" xlink:label="RevenueFromContractWithCustomerTransactionPriceAdditions" xlink:title="RevenueFromContractWithCustomerTransactionPriceAdditions" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl">The additional amount of consideration the Company earned under the collaboration agreement that is added to the transaction price.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPriceAdditions" xlink:to="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl" xlink:title="label: RevenueFromContractWithCustomerTransactionPriceAdditions to ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl1" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl1">Revenue from Contract with Customer, Transaction Price, Additions</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPriceAdditions" xlink:to="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl1" xlink:title="label: RevenueFromContractWithCustomerTransactionPriceAdditions to ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl2" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl2">Milestone payments received and added to transaction price</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPriceAdditions" xlink:to="ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl2" xlink:title="label: RevenueFromContractWithCustomerTransactionPriceAdditions to ions_RevenueFromContractWithCustomerTransactionPriceAdditions_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfPatientsUsingDrug" xlink:label="NumberOfPatientsUsingDrug" xlink:title="NumberOfPatientsUsingDrug" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfPatientsUsingDrug_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfPatientsUsingDrug_lbl" xml:lang="en-US" id="ions_NumberOfPatientsUsingDrug_lbl">The number of patients currently using the drug therapy.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfPatientsUsingDrug" xlink:to="ions_NumberOfPatientsUsingDrug_lbl" xlink:title="label: NumberOfPatientsUsingDrug to ions_NumberOfPatientsUsingDrug_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfPatientsUsingDrug_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfPatientsUsingDrug_lbl1" xml:lang="en-US" id="ions_NumberOfPatientsUsingDrug_lbl1">Number of patients using drug</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfPatientsUsingDrug" xlink:to="ions_NumberOfPatientsUsingDrug_lbl1" xlink:title="label: NumberOfPatientsUsingDrug to ions_NumberOfPatientsUsingDrug_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfPatientsUsingDrug_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfPatientsUsingDrug_lbl2" xml:lang="en-US" id="ions_NumberOfPatientsUsingDrug_lbl2">Number of patients using SPINRAZA therapy</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfPatientsUsingDrug" xlink:to="ions_NumberOfPatientsUsingDrug_lbl2" xlink:title="label: NumberOfPatientsUsingDrug to ions_NumberOfPatientsUsingDrug_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfCountriesWhereDrugIsApprovedForUse" xlink:label="NumberOfCountriesWhereDrugIsApprovedForUse" xlink:title="NumberOfCountriesWhereDrugIsApprovedForUse" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl" xml:lang="en-US" id="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl">The number of countries where the drug is approved for treatment in patients.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfCountriesWhereDrugIsApprovedForUse" xlink:to="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl" xlink:title="label: NumberOfCountriesWhereDrugIsApprovedForUse to ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl1" xml:lang="en-US" id="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl1">Number of countries where drug is approved for use</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfCountriesWhereDrugIsApprovedForUse" xlink:to="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl1" xlink:title="label: NumberOfCountriesWhereDrugIsApprovedForUse to ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl2" xml:lang="en-US" id="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl2">Number of countries where SPINRAZA is approved for use</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfCountriesWhereDrugIsApprovedForUse" xlink:to="ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl2" xlink:title="label: NumberOfCountriesWhereDrugIsApprovedForUse to ions_NumberOfCountriesWhereDrugIsApprovedForUse_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" xlink:label="CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" xlink:title="CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl" xml:lang="en-US" id="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl">Cumulative amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" xlink:to="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl" xlink:title="label: CumulativeRevenueFromContractWithCustomerExcludingAssessedTax to ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl1" xml:lang="en-US" id="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl1">Cumulative Revenue from Contract with Customer, Excluding Assessed Tax</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" xlink:to="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl1" xlink:title="label: CumulativeRevenueFromContractWithCustomerExcludingAssessedTax to ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl2" xml:lang="en-US" id="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl2">Cumulative revenue earned</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CumulativeRevenueFromContractWithCustomerExcludingAssessedTax" xlink:to="ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl2" xlink:title="label: CumulativeRevenueFromContractWithCustomerExcludingAssessedTax to ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones" xlink:label="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones" xlink:title="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl">The maximum amount of payments receivable per drug or program for regulatory milestone payments under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl1">Maximum amount of payments receivable per drug or program for regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl2">Maximum amount of payments receivable per program for regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl3" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl3" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl3">Maximum amount of payments receivable per drug for regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl3" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases" xlink:label="NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases" xlink:title="NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl" xml:lang="en-US" id="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl">The number of additional drugs in clinical development to treat neurodegenerative diseases under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases" xlink:to="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl" xlink:title="label: NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases to ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl1" xml:lang="en-US" id="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl1">Number of additional drugs in clinical development to treat neurodegenerative diseases</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases" xlink:to="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl1" xlink:title="label: NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases to ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl2" xml:lang="en-US" id="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl2">Number of additional drugs in clinical development to treat neurodegenerative diseases</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases" xlink:to="ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl2" xlink:title="label: NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases to ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PaymentsIncludedInTransactionPriceForPerformanceObligation" xlink:label="PaymentsIncludedInTransactionPriceForPerformanceObligation" xlink:title="PaymentsIncludedInTransactionPriceForPerformanceObligation" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl" xml:lang="en-US" id="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl">Total payments received since inception of the collaboration agreement included in the transaction price for the performance obligation.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsIncludedInTransactionPriceForPerformanceObligation" xlink:to="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl" xlink:title="label: PaymentsIncludedInTransactionPriceForPerformanceObligation to ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl1" xml:lang="en-US" id="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl1">Payments included in transaction price for performance obligation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsIncludedInTransactionPriceForPerformanceObligation" xlink:to="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl1" xlink:title="label: PaymentsIncludedInTransactionPriceForPerformanceObligation to ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl2" xml:lang="en-US" id="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl2">Payments included in transaction price for performance obligation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsIncludedInTransactionPriceForPerformanceObligation" xlink:to="ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl2" xlink:title="label: PaymentsIncludedInTransactionPriceForPerformanceObligation to ions_PaymentsIncludedInTransactionPriceForPerformanceObligation_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_TermOfCollaborationAgreement" xlink:label="TermOfCollaborationAgreement" xlink:title="TermOfCollaborationAgreement" />
    <link:label xlink:type="resource" xlink:label="ions_TermOfCollaborationAgreement_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_TermOfCollaborationAgreement_lbl" xml:lang="en-US" id="ions_TermOfCollaborationAgreement_lbl">Term of the collaboration agreement, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_TermOfCollaborationAgreement_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_TermOfCollaborationAgreement_lbl1" xml:lang="en-US" id="ions_TermOfCollaborationAgreement_lbl1">Term of collaboration agreement</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TermOfCollaborationAgreement" xlink:to="ions_TermOfCollaborationAgreement_lbl1" xlink:title="label: TermOfCollaborationAgreement to ions_TermOfCollaborationAgreement_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TermOfCollaborationAgreement" xlink:to="ions_TermOfCollaborationAgreement_lbl2" xlink:title="label: TermOfCollaborationAgreement to ions_TermOfCollaborationAgreement_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl">Represents information pertaining to the collaborative arrangement entered into with Biogen Inc. in December 2017 to identify new antisense oligonucleotide drug candidates for the treatment of spinal muscular atrophy, or SMA.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in December 2017 with Biogen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl1" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl2">New Antisense Drugs for the Treatment of SMA [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl">Represents information pertaining to the collaborative arrangement entered into with Biogen Inc. in January 2012 to develop and commercialize nusinersen for the treatment of spinal muscular atrophy, or SMA, a severe motor-neuron disease that is the leading genetic cause of infant mortality.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in January 2012 with Biogen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl1" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl2">SPINRAZA [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl">Represents information pertaining to the collaborative arrangement entered into with Biogen Inc. in September 2013. This agreement is a long-term strategic relationship focused on applying antisense technology to advance the treatment of neurodegenerative diseases (Strategic Neurology).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in September 2013 with Biogen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl1" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl2">2013 Strategic Neurology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl">Represents information pertaining to the expanded collaborative arrangement entered into with Biogen Inc. in April 2018 to develop novel antisense drug candidates for a broad range of neurological diseases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in April 2018 with Biogen [Member]</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl2">2018 Strategic Neurology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl">Represents information pertaining to the collaborative arrangement entered into with Biogen Inc. in December 2012. This agreement is focused on developing and commercializing novel antisense drugs for up to three targets to treat neurological or neuromuscular diseases (Neurology).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in December 2012 with Biogen [Member]</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl2">Neurology [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments" xlink:label="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments" xlink:title="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl">The maximum amount of payments receivable per drug or program for license fees and/or substantive milestone payments under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl1">Maximum amount of payments receivable per drug or program for license fees and substantive milestone payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_UpfrontPaymentReceivedIncludingPurchaseOfStock" xlink:label="UpfrontPaymentReceivedIncludingPurchaseOfStock" xlink:title="UpfrontPaymentReceivedIncludingPurchaseOfStock" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl" xml:lang="en-US" id="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl">The total amount of the upfront payment received, including the purchase of shares of the Company's stock, under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceivedIncludingPurchaseOfStock" xlink:to="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl" xlink:title="label: UpfrontPaymentReceivedIncludingPurchaseOfStock to ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl1" xml:lang="en-US" id="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl1">Upfront payment received, including purchase of stock</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceivedIncludingPurchaseOfStock" xlink:to="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl1" xlink:title="label: UpfrontPaymentReceivedIncludingPurchaseOfStock to ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl2" xml:lang="en-US" id="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl2">Upfront payment received, including purchase of stock</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceivedIncludingPurchaseOfStock" xlink:to="ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl2" xlink:title="label: UpfrontPaymentReceivedIncludingPurchaseOfStock to ions_UpfrontPaymentReceivedIncludingPurchaseOfStock_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsReceivableForSalesMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForSalesMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForSalesMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl">The maximum amount of payments receivable for sales milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForSalesMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForSalesMilestones to ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl1">Maximum amount of payments receivable for sales milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForSalesMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForSalesMilestones to ions_MaximumAmountOfPaymentsReceivableForSalesMilestones_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AntisenseMoleculeMember" xlink:label="AntisenseMoleculeMember" xlink:title="AntisenseMoleculeMember" />
    <link:label xlink:type="resource" xlink:label="ions_AntisenseMoleculeMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AntisenseMoleculeMember_lbl" xml:lang="en-US" id="ions_AntisenseMoleculeMember_lbl">Each antisense molecule that is chosen for drug discovery and development to advance the treatment of neurological diseases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AntisenseMoleculeMember" xlink:to="ions_AntisenseMoleculeMember_lbl" xlink:title="label: AntisenseMoleculeMember to ions_AntisenseMoleculeMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AntisenseMoleculeMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AntisenseMoleculeMember_lbl1" xml:lang="en-US" id="ions_AntisenseMoleculeMember_lbl1">Antisense Molecule [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AntisenseMoleculeMember" xlink:to="ions_AntisenseMoleculeMember_lbl1" xlink:title="label: AntisenseMoleculeMember to ions_AntisenseMoleculeMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfTargets" xlink:label="NumberOfTargets" xlink:title="NumberOfTargets" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfTargets_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfTargets_lbl" xml:lang="en-US" id="ions_NumberOfTargets_lbl">The number of targets for the research and development of drugs under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfTargets" xlink:to="ions_NumberOfTargets_lbl" xlink:title="label: NumberOfTargets to ions_NumberOfTargets_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfTargets_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfTargets_lbl1" xml:lang="en-US" id="ions_NumberOfTargets_lbl1">Number of targets</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfTargets" xlink:to="ions_NumberOfTargets_lbl1" xlink:title="label: NumberOfTargets to ions_NumberOfTargets_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfTargets_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfTargets_lbl2" xml:lang="en-US" id="ions_NumberOfTargets_lbl2">Number of targets</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfTargets" xlink:to="ions_NumberOfTargets_lbl2" xlink:title="label: NumberOfTargets to ions_NumberOfTargets_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones" xlink:label="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones" xlink:title="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl">The maximum amount of payments receivable per drug or program for development milestone payments under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl1">Maximum amount of payments receivable per drug or program for development milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl2">Maximum amount of payments receivable per program for development milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PremiumPaidOnSharesPurchased" xlink:label="PremiumPaidOnSharesPurchased" xlink:title="PremiumPaidOnSharesPurchased" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumPaidOnSharesPurchased_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PremiumPaidOnSharesPurchased_lbl" xml:lang="en-US" id="ions_PremiumPaidOnSharesPurchased_lbl">The cash premium paid on the purchase of the Company's common stock under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumPaidOnSharesPurchased" xlink:to="ions_PremiumPaidOnSharesPurchased_lbl" xlink:title="label: PremiumPaidOnSharesPurchased to ions_PremiumPaidOnSharesPurchased_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumPaidOnSharesPurchased_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PremiumPaidOnSharesPurchased_lbl1" xml:lang="en-US" id="ions_PremiumPaidOnSharesPurchased_lbl1">Premium paid on shares purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumPaidOnSharesPurchased" xlink:to="ions_PremiumPaidOnSharesPurchased_lbl1" xlink:title="label: PremiumPaidOnSharesPurchased to ions_PremiumPaidOnSharesPurchased_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PremiumPaidOnSharesPurchased_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PremiumPaidOnSharesPurchased_lbl2" xml:lang="en-US" id="ions_PremiumPaidOnSharesPurchased_lbl2">Premium paid on shares purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PremiumPaidOnSharesPurchased" xlink:to="ions_PremiumPaidOnSharesPurchased_lbl2" xlink:title="label: PremiumPaidOnSharesPurchased to ions_PremiumPaidOnSharesPurchased_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfDrugsCurrentlyBeingAdvanced" xlink:label="NumberOfDrugsCurrentlyBeingAdvanced" xlink:title="NumberOfDrugsCurrentlyBeingAdvanced" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl" xml:lang="en-US" id="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl">The number of drugs currently being advanced under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfDrugsCurrentlyBeingAdvanced" xlink:to="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl" xlink:title="label: NumberOfDrugsCurrentlyBeingAdvanced to ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl1" xml:lang="en-US" id="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl1">Number of drugs currently being advanced</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfDrugsCurrentlyBeingAdvanced" xlink:to="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl1" xlink:title="label: NumberOfDrugsCurrentlyBeingAdvanced to ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl2" xml:lang="en-US" id="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl2">Number of drugs currently being advanced</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfDrugsCurrentlyBeingAdvanced" xlink:to="ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl2" xlink:title="label: NumberOfDrugsCurrentlyBeingAdvanced to ions_NumberOfDrugsCurrentlyBeingAdvanced_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PercentageCashPremiumPaidOnSharesPurchased" xlink:label="PercentageCashPremiumPaidOnSharesPurchased" xlink:title="PercentageCashPremiumPaidOnSharesPurchased" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl" xml:lang="en-US" id="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl">The percentage cash premium paid per share of the Company's common stock under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageCashPremiumPaidOnSharesPurchased" xlink:to="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl" xlink:title="label: PercentageCashPremiumPaidOnSharesPurchased to ions_PercentageCashPremiumPaidOnSharesPurchased_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl1" xml:lang="en-US" id="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl1">Percentage cash premium paid on shares purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageCashPremiumPaidOnSharesPurchased" xlink:to="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl1" xlink:title="label: PercentageCashPremiumPaidOnSharesPurchased to ions_PercentageCashPremiumPaidOnSharesPurchased_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl2" xml:lang="en-US" id="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl2">Percentage cash premium paid on shares purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PercentageCashPremiumPaidOnSharesPurchased" xlink:to="ions_PercentageCashPremiumPaidOnSharesPurchased_lbl2" xlink:title="label: PercentageCashPremiumPaidOnSharesPurchased to ions_PercentageCashPremiumPaidOnSharesPurchased_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NextPotentialPayment" xlink:label="NextPotentialPayment" xlink:title="NextPotentialPayment" />
    <link:label xlink:type="resource" xlink:label="ions_NextPotentialPayment_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NextPotentialPayment_lbl" xml:lang="en-US" id="ions_NextPotentialPayment_lbl">The next potential payment to be earned under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPotentialPayment" xlink:to="ions_NextPotentialPayment_lbl" xlink:title="label: NextPotentialPayment to ions_NextPotentialPayment_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NextPotentialPayment_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NextPotentialPayment_lbl1" xml:lang="en-US" id="ions_NextPotentialPayment_lbl1">Next potential payment</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPotentialPayment" xlink:to="ions_NextPotentialPayment_lbl1" xlink:title="label: NextPotentialPayment to ions_NextPotentialPayment_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NextPotentialPayment_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NextPotentialPayment_lbl2" xml:lang="en-US" id="ions_NextPotentialPayment_lbl2">Next prospective payment</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPotentialPayment" xlink:to="ions_NextPotentialPayment_lbl2" xlink:title="label: NextPotentialPayment to ions_NextPotentialPayment_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments" xlink:label="MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments" xlink:title="MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl">The maximum amount of payments receivable per drug for substantive milestone payments under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl1">Maximum amount of payments receivable per drug for substantive milestone payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl2">Maximum amount of payments receivable per drug for substantive milestone payments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments" xlink:to="ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments to ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized" xlink:label="NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized" xlink:title="NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl" xml:lang="en-US" id="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl">The number of programs under which drugs are to be developed and commercialized under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized" xlink:to="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl" xlink:title="label: NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized to ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl1" xml:lang="en-US" id="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl1">Number of programs under which drugs are to be developed and commercialized</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized" xlink:to="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl1" xlink:title="label: NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized to ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl2" xml:lang="en-US" id="ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized_lbl2">Number of programs under which drugs are to be developed and commercialized</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement" xlink:label="RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement" xlink:title="RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement" xlink:to="ions_RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement_lbl2" xlink:title="label: RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement to ions_RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ResearchAndDevelopmentServicesForIONISFXILMember" xlink:label="ResearchAndDevelopmentServicesForIONISFXILMember" xlink:title="ResearchAndDevelopmentServicesForIONISFXILMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl">Research and development (R&amp;D) services for IONIS-FXI-L.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForIONISFXILMember" xlink:to="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl" xlink:title="label: ResearchAndDevelopmentServicesForIONISFXILMember to ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl1" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl1">Research and Development Services for IONIS-FXI-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForIONISFXILMember" xlink:to="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl1" xlink:title="label: ResearchAndDevelopmentServicesForIONISFXILMember to ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl2" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl2">R&amp;D Services for IONIS-FXI-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForIONISFXILMember" xlink:to="ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl2" xlink:title="label: ResearchAndDevelopmentServicesForIONISFXILMember to ions_ResearchAndDevelopmentServicesForIONISFXILMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_IONISFXILMember" xlink:label="IONISFXILMember" xlink:title="IONISFXILMember" />
    <link:label xlink:type="resource" xlink:label="ions_IONISFXILMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_IONISFXILMember_lbl1" xml:lang="en-US" id="ions_IONISFXILMember_lbl1">IONIS-FXI-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISFXILMember" xlink:to="ions_IONISFXILMember_lbl1" xlink:title="label: IONISFXILMember to ions_IONISFXILMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_IONISFXILMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_IONISFXILMember_lbl2" xml:lang="en-US" id="ions_IONISFXILMember_lbl2">IONIS-FXI-L [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISFXILMember" xlink:to="ions_IONISFXILMember_lbl2" xlink:title="label: IONISFXILMember to ions_IONISFXILMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_IONISFXIActivePharmaceuticalIngredientMember" xlink:label="IONISFXIActivePharmaceuticalIngredientMember" xlink:title="IONISFXIActivePharmaceuticalIngredientMember" />
    <link:label xlink:type="resource" xlink:label="ions_IONISFXIActivePharmaceuticalIngredientMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IONISFXIActivePharmaceuticalIngredientMember_lbl" xml:lang="en-US" id="ions_IONISFXIActivePharmaceuticalIngredientMember_lbl">Represents the active pharmaceutical ingredient, or API, for IONIS-FXI, an antisense drug designed to treat clotting disorders and the prevention of thrombosis.</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISFXIActivePharmaceuticalIngredientMember" xlink:to="ions_IONISFXIActivePharmaceuticalIngredientMember_lbl2" xlink:title="label: IONISFXIActivePharmaceuticalIngredientMember to ions_IONISFXIActivePharmaceuticalIngredientMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ResearchAndDevelopmentServicesForIONISFXIMember" xlink:label="ResearchAndDevelopmentServicesForIONISFXIMember" xlink:title="ResearchAndDevelopmentServicesForIONISFXIMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl">Research and development (R&amp;D) services for IONIS-FXI, an antisense drug designed to treat clotting disorders and the prevention of thrombosis.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForIONISFXIMember" xlink:to="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl" xlink:title="label: ResearchAndDevelopmentServicesForIONISFXIMember to ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl1" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl1">Research and Development Services for IONIS-FXI [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForIONISFXIMember" xlink:to="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl1" xlink:title="label: ResearchAndDevelopmentServicesForIONISFXIMember to ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl2" xml:lang="en-US" id="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl2">R&amp;D Services for IONIS-FXI [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentServicesForIONISFXIMember" xlink:to="ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl2" xlink:title="label: ResearchAndDevelopmentServicesForIONISFXIMember to ions_ResearchAndDevelopmentServicesForIONISFXIMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_IONISFXIMember" xlink:label="IONISFXIMember" xlink:title="IONISFXIMember" />
    <link:label xlink:type="resource" xlink:label="ions_IONISFXIMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IONISFXIMember_lbl" xml:lang="en-US" id="ions_IONISFXIMember_lbl">IONIS-FXI is an antisense drug designed to treat clotting disorders and the prevention of thrombosis. It targets Factor XI, a clotting factor produced in the liver that is an important component of the coagulation pathway.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISFXIMember" xlink:to="ions_IONISFXIMember_lbl" xlink:title="label: IONISFXIMember to ions_IONISFXIMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_IONISFXIMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_IONISFXIMember_lbl1" xml:lang="en-US" id="ions_IONISFXIMember_lbl1">IONIS-FXI [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISFXIMember" xlink:to="ions_IONISFXIMember_lbl1" xlink:title="label: IONISFXIMember to ions_IONISFXIMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_IONISFXIMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_IONISFXIMember_lbl2" xml:lang="en-US" id="ions_IONISFXIMember_lbl2">IONIS-FXI [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IONISFXIMember" xlink:to="ions_IONISFXIMember_lbl2" xlink:title="label: IONISFXIMember to ions_IONISFXIMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" xlink:label="CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" xlink:title="CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl">Represents information pertaining to collaborative arrangement with Bayer HealthCare amended in February 2017 to advance IONIS-FXIRx for the prevention of thrombosis and to initiate development of IONIS-FXI-LRx.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember to ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl1">Collaborative Arrangement and Licensing Agreement Amended in February 2017 with Bayer [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl1" xlink:title="label: CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember to ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl2">Bayer [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember to ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl">Represents information pertaining to collaborative arrangement entered into with Bayer HealthCare in May 2015 to develop and commercialize IONIS-FXI for the prevention of thrombosis.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in May 2015 with Bayer [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl1" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl2">Bayer [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PaymentReceivedForAdvancingPrograms" xlink:label="PaymentReceivedForAdvancingPrograms" xlink:title="PaymentReceivedForAdvancingPrograms" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivedForAdvancingPrograms_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentReceivedForAdvancingPrograms_lbl" xml:lang="en-US" id="ions_PaymentReceivedForAdvancingPrograms_lbl">The amount of payments received during the period for advancing programs under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivedForAdvancingPrograms" xlink:to="ions_PaymentReceivedForAdvancingPrograms_lbl" xlink:title="label: PaymentReceivedForAdvancingPrograms to ions_PaymentReceivedForAdvancingPrograms_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivedForAdvancingPrograms_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentReceivedForAdvancingPrograms_lbl1" xml:lang="en-US" id="ions_PaymentReceivedForAdvancingPrograms_lbl1">Payment received for advancing programs</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivedForAdvancingPrograms" xlink:to="ions_PaymentReceivedForAdvancingPrograms_lbl1" xlink:title="label: PaymentReceivedForAdvancingPrograms to ions_PaymentReceivedForAdvancingPrograms_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentReceivedForAdvancingPrograms_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PaymentReceivedForAdvancingPrograms_lbl2" xml:lang="en-US" id="ions_PaymentReceivedForAdvancingPrograms_lbl2">Payment received for advancing programs</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentReceivedForAdvancingPrograms" xlink:to="ions_PaymentReceivedForAdvancingPrograms_lbl2" xlink:title="label: PaymentReceivedForAdvancingPrograms to ions_PaymentReceivedForAdvancingPrograms_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl">Represents information pertaining to the collaborative arrangement entered into with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, in April 2013 to develop treatments for Huntington's disease, or HD, based on the Company's antisense technology.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in April 2013 with Roche [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl1" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl2">Huntington's Disease [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl">Represents information pertaining to the collaborative arrangement entered into with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, in October 2018 to develop IONIS-FB-LRx for the treatment of complement-mediated diseases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in October 2018 with Roche [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl1" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl2">IONIS-FB-L for Complement-Mediated Diseases [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_HttMember" xlink:label="HttMember" xlink:title="HttMember" />
    <link:label xlink:type="resource" xlink:label="ions_HttMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_HttMember_lbl" xml:lang="en-US" id="ions_HttMember_lbl">An antisense drug targeting huntingtin, or HTT, protein.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="HttMember" xlink:to="ions_HttMember_lbl" xlink:title="label: HttMember to ions_HttMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_HttMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_HttMember_lbl1" xml:lang="en-US" id="ions_HttMember_lbl1">IONIS-HTT [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="HttMember" xlink:to="ions_HttMember_lbl1" xlink:title="label: HttMember to ions_HttMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForCommercializationMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForCommercializationMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl">The maximum amount of payments receivable for commercialization milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForCommercializationMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForCommercializationMilestones to ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl1">Maximum amount of payments receivable for commercialization milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForCommercializationMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForCommercializationMilestones to ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl2">Maximum amount of payments receivable for commercialization milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForCommercializationMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForCommercializationMilestones to ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NextPotentialMilestonePayment" xlink:label="NextPotentialMilestonePayment" xlink:title="NextPotentialMilestonePayment" />
    <link:label xlink:type="resource" xlink:label="ions_NextPotentialMilestonePayment_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NextPotentialMilestonePayment_lbl" xml:lang="en-US" id="ions_NextPotentialMilestonePayment_lbl">The next potential milestone payment to be earned under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPotentialMilestonePayment" xlink:to="ions_NextPotentialMilestonePayment_lbl" xlink:title="label: NextPotentialMilestonePayment to ions_NextPotentialMilestonePayment_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NextPotentialMilestonePayment_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NextPotentialMilestonePayment_lbl1" xml:lang="en-US" id="ions_NextPotentialMilestonePayment_lbl1">Next potential milestone payment</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPotentialMilestonePayment" xlink:to="ions_NextPotentialMilestonePayment_lbl1" xlink:title="label: NextPotentialMilestonePayment to ions_NextPotentialMilestonePayment_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NextPotentialMilestonePayment_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NextPotentialMilestonePayment_lbl2" xml:lang="en-US" id="ions_NextPotentialMilestonePayment_lbl2">Next prospective milestone</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NextPotentialMilestonePayment" xlink:to="ions_NextPotentialMilestonePayment_lbl2" xlink:title="label: NextPotentialMilestonePayment to ions_NextPotentialMilestonePayment_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl">The maximum amount of payments receivable for development milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl1">Maximum amount of payments receivable for development milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl2">Maximum amount of payments receivable for development milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForDevelopmentMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForDevelopmentMilestones to ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MilestonePaymentsReceived" xlink:label="MilestonePaymentsReceived" xlink:title="MilestonePaymentsReceived" />
    <link:label xlink:type="resource" xlink:label="ions_MilestonePaymentsReceived_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MilestonePaymentsReceived_lbl" xml:lang="en-US" id="ions_MilestonePaymentsReceived_lbl">The amount of milestone payments received during the period under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MilestonePaymentsReceived" xlink:to="ions_MilestonePaymentsReceived_lbl" xlink:title="label: MilestonePaymentsReceived to ions_MilestonePaymentsReceived_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MilestonePaymentsReceived_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MilestonePaymentsReceived_lbl1" xml:lang="en-US" id="ions_MilestonePaymentsReceived_lbl1">Milestone payments received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MilestonePaymentsReceived" xlink:to="ions_MilestonePaymentsReceived_lbl1" xlink:title="label: MilestonePaymentsReceived to ions_MilestonePaymentsReceived_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MilestonePaymentsReceived_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MilestonePaymentsReceived_lbl2" xml:lang="en-US" id="ions_MilestonePaymentsReceived_lbl2">Milestone payments received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MilestonePaymentsReceived" xlink:to="ions_MilestonePaymentsReceived_lbl2" xlink:title="label: MilestonePaymentsReceived to ions_MilestonePaymentsReceived_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl">The maximum amount of payments receivable for license fees and substantive milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones to ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl1">Maximum amount of payments receivable for license fees and substantive milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones to ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl2">Maximum amount of payments receivable for license fees and substantive milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones to ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_UpfrontPaymentReceived" xlink:label="UpfrontPaymentReceived" xlink:title="UpfrontPaymentReceived" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceived_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_UpfrontPaymentReceived_lbl" xml:lang="en-US" id="ions_UpfrontPaymentReceived_lbl">The amount of upfront payments received during the period under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceived" xlink:to="ions_UpfrontPaymentReceived_lbl" xlink:title="label: UpfrontPaymentReceived to ions_UpfrontPaymentReceived_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceived_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_UpfrontPaymentReceived_lbl1" xml:lang="en-US" id="ions_UpfrontPaymentReceived_lbl1">Upfront payment received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceived" xlink:to="ions_UpfrontPaymentReceived_lbl1" xlink:title="label: UpfrontPaymentReceived to ions_UpfrontPaymentReceived_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_UpfrontPaymentReceived_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_UpfrontPaymentReceived_lbl2" xml:lang="en-US" id="ions_UpfrontPaymentReceived_lbl2">Upfront payment received</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UpfrontPaymentReceived" xlink:to="ions_UpfrontPaymentReceived_lbl2" xlink:title="label: UpfrontPaymentReceived to ions_UpfrontPaymentReceived_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" xlink:label="MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" xlink:title="MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl">The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsReceivableForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl1">Maximum amount of payments receivable for regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsReceivableForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl2">Maximum amount of payments receivable for regulatory milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsReceivableForRegulatoryMilestones" xlink:to="ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsReceivableForRegulatoryMilestones to ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.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-20181231.xsd#ions_RoyaltyPercentageReceivedOnNetSalesOfDrug" xlink:label="RoyaltyPercentageReceivedOnNetSalesOfDrug" xlink:title="RoyaltyPercentageReceivedOnNetSalesOfDrug" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl">Royalty percentage received on the net sales of a drug by a collaboration partner under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfDrug" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfDrug to ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl1" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl1">Royalty percentage received on net sales of drug</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfDrug" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl1" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfDrug to ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl2" xml:lang="en-US" id="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl2">Royalty percentage received on net sales of drug</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RoyaltyPercentageReceivedOnNetSalesOfDrug" xlink:to="ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl2" xlink:title="label: RoyaltyPercentageReceivedOnNetSalesOfDrug to ions_RoyaltyPercentageReceivedOnNetSalesOfDrug_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped" xlink:label="MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped" xlink:title="MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl">The maximum amount of payments receivable for each additional drug developed under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped" xlink:to="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl" xlink:title="label: MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped to ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl1">Maximum amount of payment receivable for each additional drug developed</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped" xlink:to="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl1" xlink:title="label: MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped to ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl2">Maximum amount of payment receivable for each additional drug developed</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped" xlink:to="ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl2" xlink:title="label: MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped to ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" xlink:label="RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" xlink:title="RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl">The number of separate performance obligations under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" xlink:to="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl" xlink:title="label: RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations to ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl1" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl1">Revenue from Contract with Customer, Number of separate performance obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" xlink:to="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl1" xlink:title="label: RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations to ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl2" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl2">Number of separate performance obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations" xlink:to="ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl2" xlink:title="label: RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations to ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_RevenueFromContractWithCustomerTransactionPrice" xlink:label="RevenueFromContractWithCustomerTransactionPrice" xlink:title="RevenueFromContractWithCustomerTransactionPrice" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPrice_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_RevenueFromContractWithCustomerTransactionPrice_lbl" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPrice_lbl">The amount of consideration the Company is eligible to earn under the collaboration agreement, including any variable consideration.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPrice" xlink:to="ions_RevenueFromContractWithCustomerTransactionPrice_lbl" xlink:title="label: RevenueFromContractWithCustomerTransactionPrice to ions_RevenueFromContractWithCustomerTransactionPrice_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPrice_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_RevenueFromContractWithCustomerTransactionPrice_lbl1" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPrice_lbl1">Revenue from Contract with Customer, Transaction Price</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPrice" xlink:to="ions_RevenueFromContractWithCustomerTransactionPrice_lbl1" xlink:title="label: RevenueFromContractWithCustomerTransactionPrice to ions_RevenueFromContractWithCustomerTransactionPrice_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_RevenueFromContractWithCustomerTransactionPrice_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_RevenueFromContractWithCustomerTransactionPrice_lbl2" xml:lang="en-US" id="ions_RevenueFromContractWithCustomerTransactionPrice_lbl2">Transaction price</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="RevenueFromContractWithCustomerTransactionPrice" xlink:to="ions_RevenueFromContractWithCustomerTransactionPrice_lbl2" xlink:title="label: RevenueFromContractWithCustomerTransactionPrice to ions_RevenueFromContractWithCustomerTransactionPrice_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember" xlink:label="CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember" xlink:title="CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl">Represents information pertaining to the collaborative arrangements and licensing agreements entered into with AstraZeneca PLC.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember" xlink:to="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl" xlink:title="label: CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember to ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl1">Collaborative Arrangements and Licensing Agreements, AstraZeneca [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember" xlink:to="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl1" xlink:title="label: CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember to ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl2">AstraZeneca [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember" xlink:to="ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl2" xlink:title="label: CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember to ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember" />
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    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndLicensingAgreementsRocheMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementsAndLicensingAgreementsRocheMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementsAndLicensingAgreementsRocheMember_lbl">Represents information pertaining to the collaborative arrangements and licensing agreements entered into with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche.</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember_lbl" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LossContingenciesPastSalesOfMedicationIncludedInAward" xlink:label="LossContingenciesPastSalesOfMedicationIncludedInAward" xlink:title="LossContingenciesPastSalesOfMedicationIncludedInAward" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward" xlink:label="LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward" xlink:title="LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward" />
    <link:label xlink:type="resource" xlink:label="ions_LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward_lbl" xml:lang="en-US" id="ions_LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward_lbl">Percentage applied to past sales of sofosbuvir, a medication used for the treatment of hepatitis C, used in the calculation of award to Merck Sharp &amp; Dohme Corp. and the Company by the jury.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward_lbl2" xml:lang="en-US" id="ions_LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward_lbl2">Percentage of entitled past sales of sofosbuvir included in award</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LossContingenciesNumberOfAdditionalNonJuryDefensesAsserted" xlink:label="LossContingenciesNumberOfAdditionalNonJuryDefensesAsserted" xlink:title="LossContingenciesNumberOfAdditionalNonJuryDefensesAsserted" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge" xlink:label="DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge" xlink:title="DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge" />
    <link:label xlink:type="resource" xlink:label="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge_lbl" xml:lang="en-US" id="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge_lbl">The limit of annual employee contributions to the plan per calendar year by eligible employees who are over 50 years of age.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge_lbl1" xml:lang="en-US" id="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge_lbl1">Defined Contribution Plan, Employee Contribution Limit by Plan Participants over Fifty Years Age</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge" xlink:to="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge_lbl1" xlink:title="label: DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge to ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge" xlink:to="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge_lbl2" xlink:title="label: DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge to ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge" xlink:label="DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge" xlink:title="DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge" />
    <link:label xlink:type="resource" xlink:label="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge_lbl" xml:lang="en-US" id="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge_lbl">The limit of annual employee contributions to the plan per calendar year by eligible employees who are under 50 years of age.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge_lbl1" xml:lang="en-US" id="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge_lbl1">Defined Contribution Plan, Employee Contribution Limit by Plan Participants under Fifty Years Age</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge_lbl2" xml:lang="en-US" id="ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge_lbl2">Employee contribution limit per calendar year for employees under 50 years of age</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_IncrementalCommonSharesAttributableToDilutiveEffectOfEmployeeStockPurchasePlan" xlink:label="IncrementalCommonSharesAttributableToDilutiveEffectOfEmployeeStockPurchasePlan" xlink:title="IncrementalCommonSharesAttributableToDilutiveEffectOfEmployeeStockPurchasePlan" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" xlink:label="AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" xlink:title="AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment" xlink:label="NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment" xlink:title="NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage" xlink:label="AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage" xlink:title="AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" xlink:label="AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" xlink:title="AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment" xlink:label="NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment" xlink:title="NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage" xlink:label="AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage" xlink:title="AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" xlink:label="AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" xlink:title="AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage" />
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    <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-20181231.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-20181231.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-20181231.xsd#ions_SecuritiesWithMaturityOfMoreThanOneYearMember" xlink:label="SecuritiesWithMaturityOfMoreThanOneYearMember" xlink:title="SecuritiesWithMaturityOfMoreThanOneYearMember" />
    <link:label xlink:type="resource" xlink:label="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl" xml:lang="en-US" id="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl">Represents investment securities with an expected maturity of more than one year.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SecuritiesWithMaturityOfMoreThanOneYearMember" xlink:to="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl" xlink:title="label: SecuritiesWithMaturityOfMoreThanOneYearMember to ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl1" xml:lang="en-US" id="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl1">Securities with Maturity of More than One Year [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SecuritiesWithMaturityOfMoreThanOneYearMember" xlink:to="ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl1" xlink:title="label: SecuritiesWithMaturityOfMoreThanOneYearMember to ions_SecuritiesWithMaturityOfMoreThanOneYearMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_SecuritiesWithMaturityOfOneYearOrLessMember" xlink:label="SecuritiesWithMaturityOfOneYearOrLessMember" xlink:title="SecuritiesWithMaturityOfOneYearOrLessMember" />
    <link:label xlink:type="resource" xlink:label="ions_SecuritiesWithMaturityOfOneYearOrLessMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SecuritiesWithMaturityOfOneYearOrLessMember_lbl" xml:lang="en-US" id="ions_SecuritiesWithMaturityOfOneYearOrLessMember_lbl">Represents investment securities with an expected maturity of one year or less.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SecuritiesWithMaturityOfOneYearOrLessMember" xlink:to="ions_SecuritiesWithMaturityOfOneYearOrLessMember_lbl" xlink:title="label: SecuritiesWithMaturityOfOneYearOrLessMember to ions_SecuritiesWithMaturityOfOneYearOrLessMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_SecuritiesWithMaturityOfOneYearOrLessMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SecuritiesWithMaturityOfOneYearOrLessMember_lbl1" xml:lang="en-US" id="ions_SecuritiesWithMaturityOfOneYearOrLessMember_lbl1">Securities with Maturity of One Year or Less [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SecuritiesWithMaturityOfOneYearOrLessMember" xlink:to="ions_SecuritiesWithMaturityOfOneYearOrLessMember_lbl1" xlink:title="label: SecuritiesWithMaturityOfOneYearOrLessMember to ions_SecuritiesWithMaturityOfOneYearOrLessMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementsAndLicensingAgreementsMember" xlink:label="CollaborativeArrangementsAndLicensingAgreementsMember" xlink:title="CollaborativeArrangementsAndLicensingAgreementsMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl">Represents collaborative arrangements and licensing agreements to which the entity is party.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndLicensingAgreementsMember" xlink:to="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl" xlink:title="label: CollaborativeArrangementsAndLicensingAgreementsMember to ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl1">Collaborative Arrangements and Licensing Agreements [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndLicensingAgreementsMember" xlink:to="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl1" xlink:title="label: CollaborativeArrangementsAndLicensingAgreementsMember to ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl2">Collaborative Agreements [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementsAndLicensingAgreementsMember" xlink:to="ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl2" xlink:title="label: CollaborativeArrangementsAndLicensingAgreementsMember to ions_CollaborativeArrangementsAndLicensingAgreementsMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PatentExpenses" xlink:label="PatentExpenses" xlink:title="PatentExpenses" />
    <link:label xlink:type="resource" xlink:label="ions_PatentExpenses_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PatentExpenses_lbl" xml:lang="en-US" id="ions_PatentExpenses_lbl">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="PatentExpenses" xlink:to="ions_PatentExpenses_lbl" xlink:title="label: PatentExpenses to ions_PatentExpenses_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PatentExpenses_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PatentExpenses_lbl1" xml:lang="en-US" id="ions_PatentExpenses_lbl1">Patent Expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PatentExpenses" xlink:to="ions_PatentExpenses_lbl1" xlink:title="label: PatentExpenses to ions_PatentExpenses_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PatentExpenses_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PatentExpenses_lbl2" xml:lang="en-US" id="ions_PatentExpenses_lbl2">Patent expenses</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PatentExpenses" xlink:to="ions_PatentExpenses_lbl2" xlink:title="label: PatentExpenses to ions_PatentExpenses_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PatentAbstract" xlink:label="PatentAbstract" xlink:title="PatentAbstract" />
    <link:label xlink:type="resource" xlink:label="ions_PatentAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PatentAbstract_lbl1" xml:lang="en-US" id="ions_PatentAbstract_lbl1">Patent [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PatentAbstract" xlink:to="ions_PatentAbstract_lbl1" xlink:title="label: PatentAbstract to ions_PatentAbstract_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PatentAbstract_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PatentAbstract_lbl2" xml:lang="en-US" id="ions_PatentAbstract_lbl2">Patents [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PatentAbstract" xlink:to="ions_PatentAbstract_lbl2" xlink:title="label: PatentAbstract to ions_PatentAbstract_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary" xlink:label="StockIssuedDuringPeriodSharesNewIssuesBySubsidiary" xlink:title="StockIssuedDuringPeriodSharesNewIssuesBySubsidiary" />
    <link:label xlink:type="resource" xlink:label="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl" xml:lang="en-US" id="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl">Number of new stock issued by subsidiary during the period.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodSharesNewIssuesBySubsidiary" xlink:to="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl" xlink:title="label: StockIssuedDuringPeriodSharesNewIssuesBySubsidiary to ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl1" xml:lang="en-US" id="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl1">Stock Issued During Period, Shares, New Issues by Subsidiary</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodSharesNewIssuesBySubsidiary" xlink:to="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl1" xlink:title="label: StockIssuedDuringPeriodSharesNewIssuesBySubsidiary to ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl2" xml:lang="en-US" id="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl2">Issuance of Akcea Therapeutics, Inc. common stock in conjunction with intial public offering (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodSharesNewIssuesBySubsidiary" xlink:to="ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl2" xlink:title="label: StockIssuedDuringPeriodSharesNewIssuesBySubsidiary to ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary" xlink:label="NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary" xlink:title="NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary" />
    <link:label xlink:type="resource" xlink:label="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl" xml:lang="en-US" id="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl">Amount of increase in noncontrolling interest from subsidiary issuance of equity interests to noncontrolling interest holders in an initial public offering.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary" xlink:to="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl" xlink:title="label: NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary to ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl1" xml:lang="en-US" id="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl1">Noncontrolling Interest, Increase from New Issues by Subsidiary</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary" xlink:to="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl1" xlink:title="label: NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary to ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl2" xml:lang="en-US" id="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl2">Noncontrolling interest in Akcea Therapeutics, Inc. in conjunction with initial public offering</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary" xlink:to="ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl2" xlink:title="label: NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary to ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary" xlink:label="StockIssuedDuringPeriodValueNewIssuesBySubsidiary" xlink:title="StockIssuedDuringPeriodValueNewIssuesBySubsidiary" />
    <link:label xlink:type="resource" xlink:label="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl" xml:lang="en-US" id="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl">Equity impact of the value of new stock issued during the period by a subsidiary. Includes shares issued in an initial public offering or a secondary public offering.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodValueNewIssuesBySubsidiary" xlink:to="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl" xlink:title="label: StockIssuedDuringPeriodValueNewIssuesBySubsidiary to ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl1" xml:lang="en-US" id="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl1">Stock Issued During Period, Value, New Issues by Subsidiary</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodValueNewIssuesBySubsidiary" xlink:to="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl1" xlink:title="label: StockIssuedDuringPeriodValueNewIssuesBySubsidiary to ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl2" xml:lang="en-US" id="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl2">Issuance of Akcea Therapeutics, Inc. common stock in conjunction with intial public offering</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockIssuedDuringPeriodValueNewIssuesBySubsidiary" xlink:to="ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl2" xlink:title="label: StockIssuedDuringPeriodValueNewIssuesBySubsidiary to ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption" xlink:label="AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption" xlink:title="AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption" />
    <link:label xlink:type="resource" xlink:label="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl" xml:lang="en-US" id="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl">Adjustment to additional paid in capital resulting from the redemption of convertible debt instruments as two separate components - a debt component and an equity component.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption" xlink:to="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl" xlink:title="label: AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption to ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl1" xml:lang="en-US" id="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl1">Adjustments to Additional Paid in Capital, Equity Component of Convertible Debt Redemption</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption" xlink:to="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl1" xlink:title="label: AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption to ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl2" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl2" xml:lang="en-US" id="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl2">2 3/4 percent convertible senior notes redemption, equity portion</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption" xlink:to="ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl2" xlink:title="label: AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption to ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_EmployeeStockPurchasePlanMember" xlink:label="EmployeeStockPurchasePlanMember" xlink:title="EmployeeStockPurchasePlanMember" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EmployeeStockPurchasePlanMember_lbl" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanMember_lbl">Represents the 2009 Employee Stock Purchase Plan, as amended and restated, which permits full-time employees to purchase common stock through payroll deductions at a percentage of the fair market value.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanMember" xlink:to="ions_EmployeeStockPurchasePlanMember_lbl" xlink:title="label: EmployeeStockPurchasePlanMember to ions_EmployeeStockPurchasePlanMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EmployeeStockPurchasePlanMember_lbl1" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanMember_lbl1">Employee Stock Purchase Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanMember" xlink:to="ions_EmployeeStockPurchasePlanMember_lbl1" xlink:title="label: EmployeeStockPurchasePlanMember to ions_EmployeeStockPurchasePlanMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EmployeeStockPurchasePlanMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EmployeeStockPurchasePlanMember_lbl2" xml:lang="en-US" id="ions_EmployeeStockPurchasePlanMember_lbl2">Employee Stock Purchase Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EmployeeStockPurchasePlanMember" xlink:to="ions_EmployeeStockPurchasePlanMember_lbl2" xlink:title="label: EmployeeStockPurchasePlanMember to ions_EmployeeStockPurchasePlanMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_StockOptionPlan1989Member" xlink:label="StockOptionPlan1989Member" xlink:title="StockOptionPlan1989Member" />
    <link:label xlink:type="resource" xlink:label="ions_StockOptionPlan1989Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_StockOptionPlan1989Member_lbl" xml:lang="en-US" id="ions_StockOptionPlan1989Member_lbl">Represents the 1989 Stock Option Plan, which provides the issuance of non-qualified and incentive stock options for the purchase of common stock to the entity's employees, directors and consultants.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockOptionPlan1989Member" xlink:to="ions_StockOptionPlan1989Member_lbl" xlink:title="label: StockOptionPlan1989Member to ions_StockOptionPlan1989Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_StockOptionPlan1989Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_StockOptionPlan1989Member_lbl1" xml:lang="en-US" id="ions_StockOptionPlan1989Member_lbl1">Stock Option Plan 1989 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockOptionPlan1989Member" xlink:to="ions_StockOptionPlan1989Member_lbl1" xlink:title="label: StockOptionPlan1989Member to ions_StockOptionPlan1989Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_StockOptionPlan1989Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_StockOptionPlan1989Member_lbl2" xml:lang="en-US" id="ions_StockOptionPlan1989Member_lbl2">1989 Stock Option Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockOptionPlan1989Member" xlink:to="ions_StockOptionPlan1989Member_lbl2" xlink:title="label: StockOptionPlan1989Member to ions_StockOptionPlan1989Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_EquityIncentivePlan2011Member" xlink:label="EquityIncentivePlan2011Member" xlink:title="EquityIncentivePlan2011Member" />
    <link:label xlink:type="resource" xlink:label="ions_EquityIncentivePlan2011Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EquityIncentivePlan2011Member_lbl" xml:lang="en-US" id="ions_EquityIncentivePlan2011Member_lbl">Represents the stock option plan that provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to employees, directors, and consultants.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquityIncentivePlan2011Member" xlink:to="ions_EquityIncentivePlan2011Member_lbl" xlink:title="label: EquityIncentivePlan2011Member to ions_EquityIncentivePlan2011Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EquityIncentivePlan2011Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EquityIncentivePlan2011Member_lbl1" xml:lang="en-US" id="ions_EquityIncentivePlan2011Member_lbl1">Equity Incentive Plan 2011 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquityIncentivePlan2011Member" xlink:to="ions_EquityIncentivePlan2011Member_lbl1" xlink:title="label: EquityIncentivePlan2011Member to ions_EquityIncentivePlan2011Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EquityIncentivePlan2011Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EquityIncentivePlan2011Member_lbl2" xml:lang="en-US" id="ions_EquityIncentivePlan2011Member_lbl2">2011 Equity Incentive Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquityIncentivePlan2011Member" xlink:to="ions_EquityIncentivePlan2011Member_lbl2" xlink:title="label: EquityIncentivePlan2011Member to ions_EquityIncentivePlan2011Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NonemployeeDirectorsStockOptionPlan2002Member" xlink:label="NonemployeeDirectorsStockOptionPlan2002Member" xlink:title="NonemployeeDirectorsStockOptionPlan2002Member" />
    <link:label xlink:type="resource" xlink:label="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl" xml:lang="en-US" id="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl">Represents the 2002 Non-Employee Directors Stock Option Plan, which provided for the issuance of stock options to the entity's non-employee directors for the purchase of common stock.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonemployeeDirectorsStockOptionPlan2002Member" xlink:to="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl" xlink:title="label: NonemployeeDirectorsStockOptionPlan2002Member to ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl1" xml:lang="en-US" id="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl1">Nonemployee Directors' Stock Option Plan 2002 [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonemployeeDirectorsStockOptionPlan2002Member" xlink:to="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl1" xlink:title="label: NonemployeeDirectorsStockOptionPlan2002Member to ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl2" xml:lang="en-US" id="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl2">2002 Non-Employee Directors' Stock Option Plan [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NonemployeeDirectorsStockOptionPlan2002Member" xlink:to="ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl2" xlink:title="label: NonemployeeDirectorsStockOptionPlan2002Member to ions_NonemployeeDirectorsStockOptionPlan2002Member_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable" xlink:label="NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable" xlink:title="NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable_lbl" xml:lang="en-US" id="ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable_lbl">Number of equal annual installments over which options become exercisable.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable" xlink:to="ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable_lbl" xlink:title="label: NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable to ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable_lbl1" xml:lang="en-US" id="ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable_lbl1">Number of equal annual installments over which options become exercisable</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable" xlink:to="ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable_lbl1" xlink:title="label: NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable to ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl">Represents the holding period from the date of purchase for stock purchased under the plan.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl1" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Holding Period</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl2" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl2">Holding period for purchased stock</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl2" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl">Represents the period to purchase common stock under the plan.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl1" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Purchase Period</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl2" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl2">Purchase period</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl2" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:label="PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:title="PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xml:lang="en-US" id="ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl">Period of time after a change of control of the Company when vesting will accelerate for options and RSUs outstanding as of the termination date for executive officers, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xlink:title="label: PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xml:lang="en-US" id="ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1">Period after change of control when vesting will accelerate for executive officers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xlink:title="label: PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:label="PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:title="PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xml:lang="en-US" id="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl">Period of time before a change of control of the Company when vesting will accelerate for options and RSUs outstanding as of the termination date for executive officers, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" xlink:title="label: PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xml:lang="en-US" id="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1">Period before change of control when vesting will accelerate for executive officers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" xlink:title="label: PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xml:lang="en-US" id="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2">Period before change of control when vesting will accelerate for executive officers</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers" xlink:to="ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" xlink:title="label: PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers to ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ResearchDevelopmentAndPatentMember" xlink:label="ResearchDevelopmentAndPatentMember" xlink:title="ResearchDevelopmentAndPatentMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ResearchDevelopmentAndPatentMember_lbl" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentMember_lbl">Primary financial statement caption encompassing research, development and patent expenses.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_ResearchDevelopmentAndPatentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchDevelopmentAndPatentMember_lbl1" xml:lang="en-US" id="ions_ResearchDevelopmentAndPatentMember_lbl1">Research, Development and Patent [Member]</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchDevelopmentAndPatentMember" xlink:to="ions_ResearchDevelopmentAndPatentMember_lbl2" xlink:title="label: ResearchDevelopmentAndPatentMember to ions_ResearchDevelopmentAndPatentMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CostOfProductsSoldPolicyTextBlock" xlink:label="CostOfProductsSoldPolicyTextBlock" xlink:title="CostOfProductsSoldPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="ions_CostOfProductsSoldPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CostOfProductsSoldPolicyTextBlock_lbl" xml:lang="en-US" id="ions_CostOfProductsSoldPolicyTextBlock_lbl">Disclosure of accounting policy for recognizing cost of products sold expenses.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_CostOfProductsSoldPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CostOfProductsSoldPolicyTextBlock_lbl1" xml:lang="en-US" id="ions_CostOfProductsSoldPolicyTextBlock_lbl1">Cost of Products Sold [Policy Text Block]</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_CostOfProductsSoldPolicyTextBlock_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CostOfProductsSoldPolicyTextBlock_lbl2" xml:lang="en-US" id="ions_CostOfProductsSoldPolicyTextBlock_lbl2">Cost of Products Sold</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CostOfProductsSoldPolicyTextBlock" xlink:to="ions_CostOfProductsSoldPolicyTextBlock_lbl2" xlink:title="label: CostOfProductsSoldPolicyTextBlock to ions_CostOfProductsSoldPolicyTextBlock_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock" xlink:label="CashCashEquivalentsAndInvestmentsPolicyTextBlock" xlink:title="CashCashEquivalentsAndInvestmentsPolicyTextBlock" />
    <link:label xlink:type="resource" xlink:label="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl" xml:lang="en-US" id="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl">Disclosure of accounting policy for cash, cash equivalents and investments.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CashCashEquivalentsAndInvestmentsPolicyTextBlock" xlink:to="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl" xlink:title="label: CashCashEquivalentsAndInvestmentsPolicyTextBlock to ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl1" xml:lang="en-US" id="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl1">Cash, Cash Equivalents and Investments [Policy Text Block]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CashCashEquivalentsAndInvestmentsPolicyTextBlock" xlink:to="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl1" xlink:title="label: CashCashEquivalentsAndInvestmentsPolicyTextBlock to ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl2" xml:lang="en-US" id="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl2">Cash, Cash Equivalents and Investments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CashCashEquivalentsAndInvestmentsPolicyTextBlock" xlink:to="ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl2" xlink:title="label: CashCashEquivalentsAndInvestmentsPolicyTextBlock to ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_WeightedAverageNumberOfSharesOwnedInSubsidiary" xlink:label="WeightedAverageNumberOfSharesOwnedInSubsidiary" xlink:title="WeightedAverageNumberOfSharesOwnedInSubsidiary" />
    <link:label xlink:type="resource" xlink:label="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl" xml:lang="en-US" id="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl">Number of shares owned in the subsidiary during the reporting period determined by relating the portion of time within a reporting period that shares have been owned to the total time in that period.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfSharesOwnedInSubsidiary" xlink:to="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl" xlink:title="label: WeightedAverageNumberOfSharesOwnedInSubsidiary to ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl1" xml:lang="en-US" id="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl1">Weighted average number of shares owned in subsidiary</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfSharesOwnedInSubsidiary" xlink:to="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl1" xlink:title="label: WeightedAverageNumberOfSharesOwnedInSubsidiary to ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl2" xml:lang="en-US" id="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl2">Weighted average shares owned in Akcea (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="WeightedAverageNumberOfSharesOwnedInSubsidiary" xlink:to="ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl2" xlink:title="label: WeightedAverageNumberOfSharesOwnedInSubsidiary to ions_WeightedAverageNumberOfSharesOwnedInSubsidiary_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan" xlink:label="IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan" xlink:title="IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan" />
    <link:label xlink:type="resource" xlink:label="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl" xml:lang="en-US" id="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl">Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of shares issuable related to employee stock purchase plan.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan" xlink:to="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl" xlink:title="label: IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan to ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl1" xml:lang="en-US" id="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl1">Incremental Common Shares Attributable to Employee Stock Purchase Plan</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan" xlink:to="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl1" xlink:title="label: IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan to ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl2" xml:lang="en-US" id="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl2">Shares issuable related to our ESPP (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan" xlink:to="ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl2" xlink:title="label: IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan to ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_BiogenIncMember" xlink:label="BiogenIncMember" xlink:title="BiogenIncMember" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenIncMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BiogenIncMember_lbl" xml:lang="en-US" id="ions_BiogenIncMember_lbl">Biogen Inc. is an American multinational biotechnology company.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenIncMember" xlink:to="ions_BiogenIncMember_lbl" xlink:title="label: BiogenIncMember to ions_BiogenIncMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenIncMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BiogenIncMember_lbl1" xml:lang="en-US" id="ions_BiogenIncMember_lbl1">Biogen Inc. [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenIncMember" xlink:to="ions_BiogenIncMember_lbl1" xlink:title="label: BiogenIncMember to ions_BiogenIncMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BiogenIncMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BiogenIncMember_lbl2" xml:lang="en-US" id="ions_BiogenIncMember_lbl2">Biogen [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BiogenIncMember" xlink:to="ions_BiogenIncMember_lbl2" xlink:title="label: BiogenIncMember to ions_BiogenIncMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_NovartisInternationalAGMember" xlink:label="NovartisInternationalAGMember" xlink:title="NovartisInternationalAGMember" />
    <link:label xlink:type="resource" xlink:label="ions_NovartisInternationalAGMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_NovartisInternationalAGMember_lbl" xml:lang="en-US" id="ions_NovartisInternationalAGMember_lbl">Novartis International AG is a Swiss multinational pharmaceutical company based in Basel, Switzerland.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NovartisInternationalAGMember" xlink:to="ions_NovartisInternationalAGMember_lbl" xlink:title="label: NovartisInternationalAGMember to ions_NovartisInternationalAGMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_NovartisInternationalAGMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_NovartisInternationalAGMember_lbl1" xml:lang="en-US" id="ions_NovartisInternationalAGMember_lbl1">Novartis International AG [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NovartisInternationalAGMember" xlink:to="ions_NovartisInternationalAGMember_lbl1" xlink:title="label: NovartisInternationalAGMember to ions_NovartisInternationalAGMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_NovartisInternationalAGMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_NovartisInternationalAGMember_lbl2" xml:lang="en-US" id="ions_NovartisInternationalAGMember_lbl2">Novartis [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="NovartisInternationalAGMember" xlink:to="ions_NovartisInternationalAGMember_lbl2" xlink:title="label: NovartisInternationalAGMember to ions_NovartisInternationalAGMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_UnpaidDeferredOfferingCosts" xlink:label="UnpaidDeferredOfferingCosts" xlink:title="UnpaidDeferredOfferingCosts" />
    <link:label xlink:type="resource" xlink:label="ions_UnpaidDeferredOfferingCosts_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_UnpaidDeferredOfferingCosts_lbl" xml:lang="en-US" id="ions_UnpaidDeferredOfferingCosts_lbl">Future cash outflow to pay for deferred offering costs attributable to an offering of securities that have been incurred.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UnpaidDeferredOfferingCosts" xlink:to="ions_UnpaidDeferredOfferingCosts_lbl" xlink:title="label: UnpaidDeferredOfferingCosts to ions_UnpaidDeferredOfferingCosts_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_UnpaidDeferredOfferingCosts_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_UnpaidDeferredOfferingCosts_lbl1" xml:lang="en-US" id="ions_UnpaidDeferredOfferingCosts_lbl1">Unpaid Deferred Offering Costs</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UnpaidDeferredOfferingCosts" xlink:to="ions_UnpaidDeferredOfferingCosts_lbl1" xlink:title="label: UnpaidDeferredOfferingCosts to ions_UnpaidDeferredOfferingCosts_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_UnpaidDeferredOfferingCosts_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_UnpaidDeferredOfferingCosts_lbl2" xml:lang="en-US" id="ions_UnpaidDeferredOfferingCosts_lbl2">Unpaid deferred offering costs</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="UnpaidDeferredOfferingCosts" xlink:to="ions_UnpaidDeferredOfferingCosts_lbl2" xlink:title="label: UnpaidDeferredOfferingCosts to ions_UnpaidDeferredOfferingCosts_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments" xlink:label="AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments" xlink:title="AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments" />
    <link:label xlink:type="resource" xlink:label="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl" xml:lang="en-US" id="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl">Amount of write-down of assets recognized in the income statement. Includes, but is not limited to, losses from tangible assets, intangible assets and goodwill and an other than temporary decline in value that has been recognized against investments accounted for under the cost method of accounting.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments" xlink:to="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl" xlink:title="label: AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments to ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl1" xml:lang="en-US" id="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl1">Asset Impairment Charges, including other than temporary impairment in Cost-method Investments</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl2" xml:lang="en-US" id="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl2">Non-cash losses related to patents, licensing, property, plant and equipment and strategic investments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments" xlink:to="ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl2" xlink:title="label: AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments to ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities" xlink:label="IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities" xlink:title="IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities" />
    <link:label xlink:type="resource" xlink:label="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl" xml:lang="en-US" id="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl">The increase (decrease) during the reporting period in the aggregate amount of expenses incurred but not yet paid and the change during the period in carrying value for all deferred liabilities due within one year or operating cycle.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities" xlink:to="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl" xlink:title="label: IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities to ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl1" xml:lang="en-US" id="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl1">Increase (Decrease) in Accrued Liabilities and Deferred Liabilities</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities" xlink:to="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl1" xlink:title="label: IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities to ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl2" xml:lang="en-US" id="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl2">Accrued liabilities and deferred rent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities" xlink:to="ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl2" xlink:title="label: IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities to ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PaymentToSettleFinancingLiabilityForLeasedFacility" xlink:label="PaymentToSettleFinancingLiabilityForLeasedFacility" xlink:title="PaymentToSettleFinancingLiabilityForLeasedFacility" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl" xml:lang="en-US" id="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl">The cash outflow paid to settle financing liability for leased facility.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentToSettleFinancingLiabilityForLeasedFacility" xlink:to="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl" xlink:title="label: PaymentToSettleFinancingLiabilityForLeasedFacility to ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl1" xml:lang="en-US" id="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl1">Payment to settle financing liability for leased facility</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentToSettleFinancingLiabilityForLeasedFacility" xlink:to="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl1" xlink:title="label: PaymentToSettleFinancingLiabilityForLeasedFacility to ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl2" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl2" xml:lang="en-US" id="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl2">Payment to settle financing liability for leased facility</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentToSettleFinancingLiabilityForLeasedFacility" xlink:to="ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl2" xlink:title="label: PaymentToSettleFinancingLiabilityForLeasedFacility to ions_PaymentToSettleFinancingLiabilityForLeasedFacility_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.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-20181231.xsd#ions_PaymentsToAcquireLicensesAndOtherAssets" xlink:label="PaymentsToAcquireLicensesAndOtherAssets" xlink:title="PaymentsToAcquireLicensesAndOtherAssets" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl" xml:lang="en-US" id="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl">The cash outflow for acquisition of licenses and other assets not otherwise defined in the taxonomy.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsToAcquireLicensesAndOtherAssets" xlink:to="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl" xlink:title="label: PaymentsToAcquireLicensesAndOtherAssets to ions_PaymentsToAcquireLicensesAndOtherAssets_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl1" xml:lang="en-US" id="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl1">Payments to Acquire Licenses and Other Assets</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsToAcquireLicensesAndOtherAssets" xlink:to="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl1" xlink:title="label: PaymentsToAcquireLicensesAndOtherAssets to ions_PaymentsToAcquireLicensesAndOtherAssets_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl2" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl2" xml:lang="en-US" id="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl2">Acquisition of licenses and other assets, net</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsToAcquireLicensesAndOtherAssets" xlink:to="ions_PaymentsToAcquireLicensesAndOtherAssets_lbl2" xlink:title="label: PaymentsToAcquireLicensesAndOtherAssets to ions_PaymentsToAcquireLicensesAndOtherAssets_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PaymentsToAcquireCostMethodInvestments" xlink:label="PaymentsToAcquireCostMethodInvestments" xlink:title="PaymentsToAcquireCostMethodInvestments" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsToAcquireCostMethodInvestments_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PaymentsToAcquireCostMethodInvestments_lbl" xml:lang="en-US" id="ions_PaymentsToAcquireCostMethodInvestments_lbl">The cash outflow associated with the purchase of investments accounted for under the cost method of accounting.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsToAcquireCostMethodInvestments" xlink:to="ions_PaymentsToAcquireCostMethodInvestments_lbl" xlink:title="label: PaymentsToAcquireCostMethodInvestments to ions_PaymentsToAcquireCostMethodInvestments_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsToAcquireCostMethodInvestments_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PaymentsToAcquireCostMethodInvestments_lbl1" xml:lang="en-US" id="ions_PaymentsToAcquireCostMethodInvestments_lbl1">Payments to Acquire Cost Method Investments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsToAcquireCostMethodInvestments" xlink:to="ions_PaymentsToAcquireCostMethodInvestments_lbl1" xlink:title="label: PaymentsToAcquireCostMethodInvestments to ions_PaymentsToAcquireCostMethodInvestments_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PaymentsToAcquireCostMethodInvestments_lbl2" xlink:role="http://www.xbrl.org/2009/role/negatedLabel" xlink:title="ions_PaymentsToAcquireCostMethodInvestments_lbl2" xml:lang="en-US" id="ions_PaymentsToAcquireCostMethodInvestments_lbl2">Purchase of strategic investments</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PaymentsToAcquireCostMethodInvestments" xlink:to="ions_PaymentsToAcquireCostMethodInvestments_lbl2" xlink:title="label: PaymentsToAcquireCostMethodInvestments to ions_PaymentsToAcquireCostMethodInvestments_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PotentialFuturePremium" xlink:label="PotentialFuturePremium" xlink:title="PotentialFuturePremium" />
    <link:label xlink:type="resource" xlink:label="ions_PotentialFuturePremium_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PotentialFuturePremium_lbl" xml:lang="en-US" id="ions_PotentialFuturePremium_lbl">The fair value of the potential future premium the Company will receive if Novartis purchases its common stock under a Stock Purchase Agreement (SPA) entered into in January 2017.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PotentialFuturePremium" xlink:to="ions_PotentialFuturePremium_lbl" xlink:title="label: PotentialFuturePremium to ions_PotentialFuturePremium_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PotentialFuturePremium_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PotentialFuturePremium_lbl1" xml:lang="en-US" id="ions_PotentialFuturePremium_lbl1">Potential future premium</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PotentialFuturePremium" xlink:to="ions_PotentialFuturePremium_lbl1" xlink:title="label: PotentialFuturePremium to ions_PotentialFuturePremium_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PotentialFuturePremium_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PotentialFuturePremium_lbl2" xml:lang="en-US" id="ions_PotentialFuturePremium_lbl2">Fair value of potential future premium</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PotentialFuturePremium" xlink:to="ions_PotentialFuturePremium_lbl2" xlink:title="label: PotentialFuturePremium to ions_PotentialFuturePremium_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AdditionalAmountOfCommonStockRequiredToBePurchased" xlink:label="AdditionalAmountOfCommonStockRequiredToBePurchased" xlink:title="AdditionalAmountOfCommonStockRequiredToBePurchased" />
    <link:label xlink:type="resource" xlink:label="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl" xml:lang="en-US" id="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl">The additional amount of common stock the collaboration partner is required to purchase under a Stock Purchase Agreement (SPA) in conjunction with the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AdditionalAmountOfCommonStockRequiredToBePurchased" xlink:to="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl" xlink:title="label: AdditionalAmountOfCommonStockRequiredToBePurchased to ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl1" xml:lang="en-US" id="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl1">Additional amount of common stock required to be purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AdditionalAmountOfCommonStockRequiredToBePurchased" xlink:to="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl1" xlink:title="label: AdditionalAmountOfCommonStockRequiredToBePurchased to ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl2" xml:lang="en-US" id="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl2">Additional amount of common stock required to be purchased</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AdditionalAmountOfCommonStockRequiredToBePurchased" xlink:to="ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl2" xlink:title="label: AdditionalAmountOfCommonStockRequiredToBePurchased to ions_AdditionalAmountOfCommonStockRequiredToBePurchased_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_FutureStockPurchaseAbstract" xlink:label="FutureStockPurchaseAbstract" xlink:title="FutureStockPurchaseAbstract" />
    <link:label xlink:type="resource" xlink:label="ions_FutureStockPurchaseAbstract_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_FutureStockPurchaseAbstract_lbl1" xml:lang="en-US" id="ions_FutureStockPurchaseAbstract_lbl1">Future Stock Purchase [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="FutureStockPurchaseAbstract" xlink:to="ions_FutureStockPurchaseAbstract_lbl1" xlink:title="label: FutureStockPurchaseAbstract to ions_FutureStockPurchaseAbstract_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_FutureStockPurchaseAbstract_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_FutureStockPurchaseAbstract_lbl2" xml:lang="en-US" id="ions_FutureStockPurchaseAbstract_lbl2">Novartis Future Stock Purchase [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="FutureStockPurchaseAbstract" xlink:to="ions_FutureStockPurchaseAbstract_lbl2" xlink:title="label: FutureStockPurchaseAbstract to ions_FutureStockPurchaseAbstract_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl">Represents information pertaining to the collaborative arrangements and licensing agreements entered into with Novartis to develop and commercialize AKCEA-APO(a)-L and AKCEA-APOCIII-L.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in January 2017 with Novartis [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl1" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl2">Novartis [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PotentialFuturePremiumMember" xlink:label="PotentialFuturePremiumMember" xlink:title="PotentialFuturePremiumMember" />
    <link:label xlink:type="resource" xlink:label="ions_PotentialFuturePremiumMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PotentialFuturePremiumMember_lbl" xml:lang="en-US" id="ions_PotentialFuturePremiumMember_lbl">The potential future premium that will be received if Novartis purchases the Company's common stock at a percentage premium over the trading price of the common stock at the time of purchase under the terms of a Stock Purchase Agreement (SPA).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PotentialFuturePremiumMember" xlink:to="ions_PotentialFuturePremiumMember_lbl" xlink:title="label: PotentialFuturePremiumMember to ions_PotentialFuturePremiumMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PotentialFuturePremiumMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PotentialFuturePremiumMember_lbl1" xml:lang="en-US" id="ions_PotentialFuturePremiumMember_lbl1">Potential Future Premium [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PotentialFuturePremiumMember" xlink:to="ions_PotentialFuturePremiumMember_lbl1" xlink:title="label: PotentialFuturePremiumMember to ions_PotentialFuturePremiumMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PotentialFuturePremiumMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PotentialFuturePremiumMember_lbl2" xml:lang="en-US" id="ions_PotentialFuturePremiumMember_lbl2">Potential Future Premium [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PotentialFuturePremiumMember" xlink:to="ions_PotentialFuturePremiumMember_lbl2" xlink:title="label: PotentialFuturePremiumMember to ions_PotentialFuturePremiumMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue" xlink:label="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue" xlink:title="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl">The weighted average grant-date fair value of options exercised during the reporting period as calculated by applying the disclosed option pricing methodology.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl1" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl1">Share-based Compensation Arrangement by Share-based Payment Award, Options, Exercises in Period, Weighted Average Fair Value</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl1" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl2" xml:lang="en-US" id="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl2">Weighted-average fair value of options exercised (in dollars per share)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue" xlink:to="ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl2" xlink:title="label: ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue to ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_IonisCoreMember" xlink:label="IonisCoreMember" xlink:title="IonisCoreMember" />
    <link:label xlink:type="resource" xlink:label="ions_IonisCoreMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_IonisCoreMember_lbl" xml:lang="en-US" id="ions_IonisCoreMember_lbl">Reportable segment in which the Company is exploiting a novel drug discovery platform created to generate a broad pipeline of first-in-class or best-in-class drugs for the Company and its partners. This segment generates revenue from a multifaceted partnering strategy. This strategy includes revenue from collaborations with preferred partners, traditional alliances and working with a consortium of companies that can exploit the Company's drugs and technology. Revenue from collaborations with preferred partners and traditional alliances may consist of upfront payments, milestone payments, licensing fees and royalties.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IonisCoreMember" xlink:to="ions_IonisCoreMember_lbl" xlink:title="label: IonisCoreMember to ions_IonisCoreMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_IonisCoreMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_IonisCoreMember_lbl1" xml:lang="en-US" id="ions_IonisCoreMember_lbl1">Ionis Core [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IonisCoreMember" xlink:to="ions_IonisCoreMember_lbl1" xlink:title="label: IonisCoreMember to ions_IonisCoreMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_IonisCoreMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_IonisCoreMember_lbl2" xml:lang="en-US" id="ions_IonisCoreMember_lbl2">Ionis [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="IonisCoreMember" xlink:to="ions_IonisCoreMember_lbl2" xlink:title="label: IonisCoreMember to ions_IonisCoreMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_AkceaTherapeuticsMember" xlink:label="AkceaTherapeuticsMember" xlink:title="AkceaTherapeuticsMember" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaTherapeuticsMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AkceaTherapeuticsMember_lbl" xml:lang="en-US" id="ions_AkceaTherapeuticsMember_lbl">Reportable segment which includes the operations of the Company's wholly-owned subsidiary, Akcea Therapeutics, Inc., which was formed to develop and commercialize drugs for cardiometabolic disorders.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaTherapeuticsMember" xlink:to="ions_AkceaTherapeuticsMember_lbl" xlink:title="label: AkceaTherapeuticsMember to ions_AkceaTherapeuticsMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaTherapeuticsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AkceaTherapeuticsMember_lbl1" xml:lang="en-US" id="ions_AkceaTherapeuticsMember_lbl1">Akcea Therapeutics [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaTherapeuticsMember" xlink:to="ions_AkceaTherapeuticsMember_lbl1" xlink:title="label: AkceaTherapeuticsMember to ions_AkceaTherapeuticsMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_BoardOfDirectorStockOptionMember" xlink:label="BoardOfDirectorStockOptionMember" xlink:title="BoardOfDirectorStockOptionMember" />
    <link:label xlink:type="resource" xlink:label="ions_BoardOfDirectorStockOptionMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_BoardOfDirectorStockOptionMember_lbl" xml:lang="en-US" id="ions_BoardOfDirectorStockOptionMember_lbl">An arrangement whereby a member of the Board of Directors is entitled to receive in the future, subject to vesting and other restrictions, a number of shares in the entity at a specified price, as defined in the agreement, as a form of compensation.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BoardOfDirectorStockOptionMember" xlink:to="ions_BoardOfDirectorStockOptionMember_lbl" xlink:title="label: BoardOfDirectorStockOptionMember to ions_BoardOfDirectorStockOptionMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_BoardOfDirectorStockOptionMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_BoardOfDirectorStockOptionMember_lbl1" xml:lang="en-US" id="ions_BoardOfDirectorStockOptionMember_lbl1">Board of Director Stock Option [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BoardOfDirectorStockOptionMember" xlink:to="ions_BoardOfDirectorStockOptionMember_lbl1" xlink:title="label: BoardOfDirectorStockOptionMember to ions_BoardOfDirectorStockOptionMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_BoardOfDirectorStockOptionMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_BoardOfDirectorStockOptionMember_lbl2" xml:lang="en-US" id="ions_BoardOfDirectorStockOptionMember_lbl2">Board of Director Stock Options [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="BoardOfDirectorStockOptionMember" xlink:to="ions_BoardOfDirectorStockOptionMember_lbl2" xlink:title="label: BoardOfDirectorStockOptionMember to ions_BoardOfDirectorStockOptionMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ShareBasedCompensationLineItems" xlink:label="ShareBasedCompensationLineItems" xlink:title="ShareBasedCompensationLineItems" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationLineItems_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ShareBasedCompensationLineItems_lbl" xml:lang="en-US" id="ions_ShareBasedCompensationLineItems_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="ShareBasedCompensationLineItems" xlink:to="ions_ShareBasedCompensationLineItems_lbl" xlink:title="label: ShareBasedCompensationLineItems to ions_ShareBasedCompensationLineItems_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationLineItems_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ShareBasedCompensationLineItems_lbl1" xml:lang="en-US" id="ions_ShareBasedCompensationLineItems_lbl1">Share-based Compensation [Line Items]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationLineItems" xlink:to="ions_ShareBasedCompensationLineItems_lbl1" xlink:title="label: ShareBasedCompensationLineItems to ions_ShareBasedCompensationLineItems_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ShareBasedCompensationLineItems_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ShareBasedCompensationLineItems_lbl2" xml:lang="en-US" id="ions_ShareBasedCompensationLineItems_lbl2">Stockholders' Equity [Abstract]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ShareBasedCompensationLineItems" xlink:to="ions_ShareBasedCompensationLineItems_lbl2" xlink:title="label: ShareBasedCompensationLineItems to ions_ShareBasedCompensationLineItems_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_StockTable" xlink:label="StockTable" xlink:title="StockTable" />
    <link:label xlink:type="resource" xlink:label="ions_StockTable_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_StockTable_lbl" xml:lang="en-US" id="ions_StockTable_lbl">Disclosure of information about share-based compensation.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockTable" xlink:to="ions_StockTable_lbl" xlink:title="label: StockTable to ions_StockTable_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_StockTable_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_StockTable_lbl1" xml:lang="en-US" id="ions_StockTable_lbl1">Share-based Compensation [Table]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="StockTable" xlink:to="ions_StockTable_lbl1" xlink:title="label: StockTable to ions_StockTable_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PrimaryResearchAndDevelopmentFacilityMember" xlink:label="PrimaryResearchAndDevelopmentFacilityMember" xlink:title="PrimaryResearchAndDevelopmentFacilityMember" />
    <link:label xlink:type="resource" xlink:label="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl" xml:lang="en-US" id="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl">Facility constructed for the entity's primary research and development activities under a lease agreement with an affiliate of BioMed Realty, L.P.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PrimaryResearchAndDevelopmentFacilityMember" xlink:to="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl" xlink:title="label: PrimaryResearchAndDevelopmentFacilityMember to ions_PrimaryResearchAndDevelopmentFacilityMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl1" xml:lang="en-US" id="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl1">Primary Research and Development Facility [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PrimaryResearchAndDevelopmentFacilityMember" xlink:to="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl1" xlink:title="label: PrimaryResearchAndDevelopmentFacilityMember to ions_PrimaryResearchAndDevelopmentFacilityMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl2" xml:lang="en-US" id="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl2">Primary R&amp;D Facility [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PrimaryResearchAndDevelopmentFacilityMember" xlink:to="ions_PrimaryResearchAndDevelopmentFacilityMember_lbl2" xlink:title="label: PrimaryResearchAndDevelopmentFacilityMember to ions_PrimaryResearchAndDevelopmentFacilityMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" xlink:label="PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" xlink:title="PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl" xml:lang="en-US" id="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl">Period of time to make only payments of interest on the mortgage loan, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" xlink:to="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl" xlink:title="label: PeriodToMakeInterestOnlyPaymentsOnMortgageLoan to ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl1" xml:lang="en-US" id="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl1">Period to make interest only payments on mortgage loan</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" xlink:to="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl1" xlink:title="label: PeriodToMakeInterestOnlyPaymentsOnMortgageLoan to ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl2" xml:lang="en-US" id="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl2">Period to make interest only payments on mortgage loan</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PeriodToMakeInterestOnlyPaymentsOnMortgageLoan" xlink:to="ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl2" xlink:title="label: PeriodToMakeInterestOnlyPaymentsOnMortgageLoan to ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_EquipmentAndComputerSoftwareMember" xlink:label="EquipmentAndComputerSoftwareMember" xlink:title="EquipmentAndComputerSoftwareMember" />
    <link:label xlink:type="resource" xlink:label="ions_EquipmentAndComputerSoftwareMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EquipmentAndComputerSoftwareMember_lbl" xml:lang="en-US" id="ions_EquipmentAndComputerSoftwareMember_lbl">Long lived, depreciable assets that are used in the creation, maintenance and utilization of information systems and purchased software applications and internally developed software for long-term internal use. Includes other tangible personal property, nonconsumable in nature, with finite lives used to produce goods and services, such as laboratory, manufacturing and other equipment.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquipmentAndComputerSoftwareMember" xlink:to="ions_EquipmentAndComputerSoftwareMember_lbl" xlink:title="label: EquipmentAndComputerSoftwareMember to ions_EquipmentAndComputerSoftwareMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_EquipmentAndComputerSoftwareMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_EquipmentAndComputerSoftwareMember_lbl1" xml:lang="en-US" id="ions_EquipmentAndComputerSoftwareMember_lbl1">Equipment and Computer Software [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquipmentAndComputerSoftwareMember" xlink:to="ions_EquipmentAndComputerSoftwareMember_lbl1" xlink:title="label: EquipmentAndComputerSoftwareMember to ions_EquipmentAndComputerSoftwareMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_EquipmentAndComputerSoftwareMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_EquipmentAndComputerSoftwareMember_lbl2" xml:lang="en-US" id="ions_EquipmentAndComputerSoftwareMember_lbl2">Computer Software, Laboratory, Manufacturing and Other Equipment [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EquipmentAndComputerSoftwareMember" xlink:to="ions_EquipmentAndComputerSoftwareMember_lbl2" xlink:title="label: EquipmentAndComputerSoftwareMember to ions_EquipmentAndComputerSoftwareMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_PropertyPlantAndEquipmentExcludingLandMember" xlink:label="PropertyPlantAndEquipmentExcludingLandMember" xlink:title="PropertyPlantAndEquipmentExcludingLandMember" />
    <link:label xlink:type="resource" xlink:label="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl" xml:lang="en-US" id="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl">Physical assets used in the normal conduct of business and not intended for resale, excluding land. Examples include, but are not limited to, buildings, land and leasehold improvements, machinery and equipment, office equipment, and furniture and fixtures.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentExcludingLandMember" xlink:to="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl" xlink:title="label: PropertyPlantAndEquipmentExcludingLandMember to ions_PropertyPlantAndEquipmentExcludingLandMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl1" xml:lang="en-US" id="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl1">Property, Plant and Equipment, Excluding Land [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="PropertyPlantAndEquipmentExcludingLandMember" xlink:to="ions_PropertyPlantAndEquipmentExcludingLandMember_lbl1" xlink:title="label: PropertyPlantAndEquipmentExcludingLandMember to ions_PropertyPlantAndEquipmentExcludingLandMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember" xlink:label="LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember" xlink:title="LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember_lbl" xml:lang="en-US" id="ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember_lbl">Represents the aggregate of all long-term obligations of the entity, including capital leases and other financing arrangements, excluding the long-term financing liability for the entity's leased research and development facility.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember" xlink:to="ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember_lbl" xlink:title="label: LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember to ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember_lbl1" xml:lang="en-US" id="ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember_lbl1">Long-Term Obligations, Excluding Financing Liability for Leased Facility [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember" xlink:to="ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember_lbl1" xlink:title="label: LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember to ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange" xlink:label="DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange" xlink:title="DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange" />
    <link:label xlink:type="resource" xlink:label="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange_lbl" xml:lang="en-US" id="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange_lbl">The percentage of the principal amount of the notes to be purchased, plus accrued and unpaid interest, upon the occurrence of certain fundamental changes, as set forth in the indenture governing the convertible notes.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange" xlink:to="ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange_lbl" xlink:title="label: DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange to ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange_lbl" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_EffectiveIncomeTaxRateReconciliationDeconsolidationAdjustmentForSubsidiaryAtIPOAmount" xlink:label="EffectiveIncomeTaxRateReconciliationDeconsolidationAdjustmentForSubsidiaryAtIPOAmount" xlink:title="EffectiveIncomeTaxRateReconciliationDeconsolidationAdjustmentForSubsidiaryAtIPOAmount" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount" xlink:label="EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount" xlink:title="EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount" />
    <link:label xlink:type="resource" xlink:label="ions_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount_lbl" xml:lang="en-US" id="ions_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount_lbl">Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to the expiration of net operating loss carryforwards.</link:label>
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount" xlink:to="ions_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount_lbl2" xlink:title="label: EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount to ions_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance" xlink:label="DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance" xlink:title="DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance" />
    <link:label xlink:type="resource" xlink:label="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl" xml:lang="en-US" id="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl">Represents the net amount of deferred tax assets (before reduction for valuation allowance) and liabilities as of the balance sheet date, which result from applying the applicable enacted tax rate to net temporary differences and carryforwards pertaining to assets or liabilities.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl1" xml:lang="en-US" id="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl1">Deferred Tax Assets (Liabilities), Net, before Valuation Allowance</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance" xlink:to="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl1" xlink:title="label: DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance to ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl2" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl2" xml:lang="en-US" id="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl2">Net deferred tax asset</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance" xlink:to="ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl2" xlink:title="label: DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance to ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_OperatingLossCarryforwardsUtilizationPeriod" xlink:label="OperatingLossCarryforwardsUtilizationPeriod" xlink:title="OperatingLossCarryforwardsUtilizationPeriod" />
    <link:label xlink:type="resource" xlink:label="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl" xml:lang="en-US" id="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl">Period of time before operating loss carryforwards and tax credit carryforwards will be utilized, in PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl1" xml:lang="en-US" id="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl1">Operating Loss Carryforwards, Utilization Period</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLossCarryforwardsUtilizationPeriod" xlink:to="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl1" xlink:title="label: OperatingLossCarryforwardsUtilizationPeriod to ions_OperatingLossCarryforwardsUtilizationPeriod_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl2" xml:lang="en-US" id="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl2">Utilization period for net operating loss carryforwards and tax credit carryforwards</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OperatingLossCarryforwardsUtilizationPeriod" xlink:to="ions_OperatingLossCarryforwardsUtilizationPeriod_lbl2" xlink:title="label: OperatingLossCarryforwardsUtilizationPeriod to ions_OperatingLossCarryforwardsUtilizationPeriod_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" xlink:label="ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" xlink:title="ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl1" xml:lang="en-US" id="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl1">Research and Development Revenue Under Collaborative Agreements [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" xlink:to="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl1" xlink:title="label: ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember to ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/verboseLabel" xlink:title="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl2" xml:lang="en-US" id="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl2">R&amp;D Revenue Under Collaborative Agreements [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember" xlink:to="ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl2" xlink:title="label: ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember to ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember_lbl2" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LicensingAndOtherRoyaltiesMember" xlink:label="LicensingAndOtherRoyaltiesMember" xlink:title="LicensingAndOtherRoyaltiesMember" />
    <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" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LicensingAndOtherRoyaltiesMember" xlink:to="ions_LicensingAndOtherRoyaltiesMember_lbl2" xlink:title="label: LicensingAndOtherRoyaltiesMember to ions_LicensingAndOtherRoyaltiesMember_lbl2" />
    <link:label xlink:type="resource" xlink:label="ions_LicensingAndOtherRoyaltiesMember_lbl3" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LicensingAndOtherRoyaltiesMember_lbl3" xml:lang="en-US" id="ions_LicensingAndOtherRoyaltiesMember_lbl3">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_lbl3" xlink:title="label: LicensingAndOtherRoyaltiesMember to ions_LicensingAndOtherRoyaltiesMember_lbl3" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_SPINRAZARoyaltiesMember" xlink:label="SPINRAZARoyaltiesMember" xlink:title="SPINRAZARoyaltiesMember" />
    <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-20181231.xsd#ions_CommercialMember" xlink:label="CommercialMember" xlink:title="CommercialMember" />
    <link:label xlink:type="resource" xlink:label="ions_CommercialMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CommercialMember_lbl1" xml:lang="en-US" id="ions_CommercialMember_lbl1">Commercial [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CommercialMember" xlink:to="ions_CommercialMember_lbl1" xlink:title="label: CommercialMember to ions_CommercialMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CommercialMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CommercialMember_lbl2" xml:lang="en-US" id="ions_CommercialMember_lbl2">Commercial Revenue [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CommercialMember" xlink:to="ions_CommercialMember_lbl2" xlink:title="label: CommercialMember to ions_CommercialMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_GainLossOnExtinguishmentOfFinancingLiability" xlink:label="GainLossOnExtinguishmentOfFinancingLiability" xlink:title="GainLossOnExtinguishmentOfFinancingLiability" />
    <link:label xlink:type="resource" xlink:label="ions_GainLossOnExtinguishmentOfFinancingLiability_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_GainLossOnExtinguishmentOfFinancingLiability_lbl" xml:lang="en-US" id="ions_GainLossOnExtinguishmentOfFinancingLiability_lbl">Difference between the purchase price of the facility and the carrying value of our financing liability at the time of the purchase.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_GainLossOnExtinguishmentOfFinancingLiability_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_GainLossOnExtinguishmentOfFinancingLiability_lbl1" xml:lang="en-US" id="ions_GainLossOnExtinguishmentOfFinancingLiability_lbl1">Gain (Loss) on Extinguishment of Financing Liability</link:label>
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ResearchDevelopmentAndPatentExpense" xlink:label="ResearchDevelopmentAndPatentExpense" xlink:title="ResearchDevelopmentAndPatentExpense" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CumulativeCostOfProductsSold" xlink:label="CumulativeCostOfProductsSold" xlink:title="CumulativeCostOfProductsSold" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_TaxCutsAndJobsActOf2017IncompleteAccountingChangeInTaxRateProvisionalIncomeTaxExpenseBenefit" xlink:label="TaxCutsAndJobsActOf2017IncompleteAccountingChangeInTaxRateProvisionalIncomeTaxExpenseBenefit" xlink:title="TaxCutsAndJobsActOf2017IncompleteAccountingChangeInTaxRateProvisionalIncomeTaxExpenseBenefit" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation" xlink:label="LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation" xlink:title="LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation_lbl" xml:lang="en-US" id="ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation_lbl">Initial letter of credit provided to lessor to secure lease obligation under lessee's operating lease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation" xlink:to="ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation_lbl" xlink:title="label: LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation to ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation_lbl1" xml:lang="en-US" id="ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation_lbl1">Lessee, Operating Lease, Initial Letter of Credit to Secure Lease Obligation</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation" xlink:to="ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation_lbl1" xlink:title="label: LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation to ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation_lbl1" />
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    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate" xlink:label="LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate" xlink:title="LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl" xml:lang="en-US" id="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl">Letter of credit provided to lessor to secure lease obligation under lessee's operating lease on the third anniversary of the rent commencement date.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate" xlink:to="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl" xlink:title="label: LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate to ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl1" xml:lang="en-US" id="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl1">Lessee, Operating Lease, Letter of Credit to Secure Lease Obligation on Third Anniversary of Rent Commencement Date</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate" xlink:to="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl1" xlink:title="label: LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate to ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl2" xml:lang="en-US" id="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl2">Letter of credit on third anniversary of rent commencement date</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate" xlink:to="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl2" xlink:title="label: LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate to ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate" xlink:label="LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate" xlink:title="LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl" xml:lang="en-US" id="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl">Letter of credit provided to lessor to secure lease obligation under lessee's operating lease on the fifth anniversary of the rent commencement date.</link:label>
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    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl1" xml:lang="en-US" id="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl1">Lessee, Operating Lease, Letter of Credit to Secure Lease Obligation on Fifth Anniversary of Rent Commencement Date</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate" xlink:to="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl1" xlink:title="label: LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate to ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl2" xml:lang="en-US" id="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl2">Letter of credit on fifth anniversary of rent commencement date</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate" xlink:to="ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl2" xlink:title="label: LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate to ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LesseeOperatingLeaseAllowanceForTenantImprovements" xlink:label="LesseeOperatingLeaseAllowanceForTenantImprovements" xlink:title="LesseeOperatingLeaseAllowanceForTenantImprovements" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl" xml:lang="en-US" id="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl">Allowance for tenant improvements to the office space included in the lessee's operating lease.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseAllowanceForTenantImprovements" xlink:to="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl" xlink:title="label: LesseeOperatingLeaseAllowanceForTenantImprovements to ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl1" xml:lang="en-US" id="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl1">Lessee, Operating Lease, Allowance for Tenant Improvements</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseAllowanceForTenantImprovements" xlink:to="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl1" xlink:title="label: LesseeOperatingLeaseAllowanceForTenantImprovements to ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl1" />
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    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeaseAllowanceForTenantImprovements" xlink:to="ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl2" xlink:title="label: LesseeOperatingLeaseAllowanceForTenantImprovements to ions_LesseeOperatingLeaseAllowanceForTenantImprovements_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LesseeOperatingLeasePeriodOfFreeRent" xlink:label="LesseeOperatingLeasePeriodOfFreeRent" xlink:title="LesseeOperatingLeasePeriodOfFreeRent" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl" xml:lang="en-US" id="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl">Period of time in which the rent is free under operating lease, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeasePeriodOfFreeRent" xlink:to="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl" xlink:title="label: LesseeOperatingLeasePeriodOfFreeRent to ions_LesseeOperatingLeasePeriodOfFreeRent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl1" xml:lang="en-US" id="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl1">Lessee, Operating Lease, Period of Free Rent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeasePeriodOfFreeRent" xlink:to="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl1" xlink:title="label: LesseeOperatingLeasePeriodOfFreeRent to ions_LesseeOperatingLeasePeriodOfFreeRent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl2" xml:lang="en-US" id="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl2">Period of free rent under lease</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeOperatingLeasePeriodOfFreeRent" xlink:to="ions_LesseeOperatingLeasePeriodOfFreeRent_lbl2" xlink:title="label: LesseeOperatingLeasePeriodOfFreeRent to ions_LesseeOperatingLeasePeriodOfFreeRent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_OfficeSpaceForCorporateHeadquartersMember" xlink:label="OfficeSpaceForCorporateHeadquartersMember" xlink:title="OfficeSpaceForCorporateHeadquartersMember" />
    <link:label xlink:type="resource" xlink:label="ions_OfficeSpaceForCorporateHeadquartersMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_OfficeSpaceForCorporateHeadquartersMember_lbl" xml:lang="en-US" id="ions_OfficeSpaceForCorporateHeadquartersMember_lbl">Office space located in Boston, Massachusetts for Akcea Therapeutics, Inc.'s corporate headquarters leased under non-cancelable operating leases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OfficeSpaceForCorporateHeadquartersMember" xlink:to="ions_OfficeSpaceForCorporateHeadquartersMember_lbl" xlink:title="label: OfficeSpaceForCorporateHeadquartersMember to ions_OfficeSpaceForCorporateHeadquartersMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_OfficeSpaceForCorporateHeadquartersMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_OfficeSpaceForCorporateHeadquartersMember_lbl1" xml:lang="en-US" id="ions_OfficeSpaceForCorporateHeadquartersMember_lbl1">Office Space for Corporate Headquarters [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OfficeSpaceForCorporateHeadquartersMember" xlink:to="ions_OfficeSpaceForCorporateHeadquartersMember_lbl1" xlink:title="label: OfficeSpaceForCorporateHeadquartersMember to ions_OfficeSpaceForCorporateHeadquartersMember_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember" xlink:label="OfficeSpaceSubleasedToAkceaTherapeuticsIncMember" xlink:title="OfficeSpaceSubleasedToAkceaTherapeuticsIncMember" />
    <link:label xlink:type="resource" xlink:label="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl" xml:lang="en-US" id="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl">Office space subleased to Akcea Therapeutics, Inc. (Akcea) leased under non-cancelable operating leases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OfficeSpaceSubleasedToAkceaTherapeuticsIncMember" xlink:to="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl" xlink:title="label: OfficeSpaceSubleasedToAkceaTherapeuticsIncMember to ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl1" xml:lang="en-US" id="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl1">Office Space Subleased to Akcea Therapeutics, Inc. [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OfficeSpaceSubleasedToAkceaTherapeuticsIncMember" xlink:to="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl1" xlink:title="label: OfficeSpaceSubleasedToAkceaTherapeuticsIncMember to ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl2" xml:lang="en-US" id="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl2">Office Space Subleased to Akcea [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OfficeSpaceSubleasedToAkceaTherapeuticsIncMember" xlink:to="ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl2" xlink:title="label: OfficeSpaceSubleasedToAkceaTherapeuticsIncMember to ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember" xlink:label="OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember" xlink:title="OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember" />
    <link:label xlink:type="resource" xlink:label="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl" xml:lang="en-US" id="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl">Office and laboratory space in a facility adjacent to the Company's manufacturing facility leased under non-cancelable operating leases.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember" xlink:to="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl" xlink:title="label: OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember to ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl1" xml:lang="en-US" id="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl1">Office and Laboratory Space Adjacent to Manufacturing Facility [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember" xlink:to="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl1" xlink:title="label: OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember to ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl2" xml:lang="en-US" id="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl2">Office and Laboratory Space Adjacent to Manufacturing Facility [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember" xlink:to="ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl2" xlink:title="label: OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember to ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" xlink:label="LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" xlink:title="LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl" xml:lang="en-US" id="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl">The number of options to extend the lease under the lessee's operating leasing arrangement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" xlink:to="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl" xlink:title="label: LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease to ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl1" xml:lang="en-US" id="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl1">Lessee Leasing Arrangements, Operating Leases, Number of options to extend lease</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" xlink:to="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl1" xlink:title="label: LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease to ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl2" xml:lang="en-US" id="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl2">Number of options to extend lease</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease" xlink:to="ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl2" xlink:title="label: LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease to ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LongTermObligationsNoncurrent" xlink:label="LongTermObligationsNoncurrent" xlink:title="LongTermObligationsNoncurrent" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsNoncurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermObligationsNoncurrent_lbl" xml:lang="en-US" id="ions_LongTermObligationsNoncurrent_lbl">Carrying amount of long-term obligations due in the next twelve months or greater than the normal operating cycle, if longer, excluding convertible senior notes and a long-term financing liability for a leased facility.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsNoncurrent" xlink:to="ions_LongTermObligationsNoncurrent_lbl" xlink:title="label: LongTermObligationsNoncurrent to ions_LongTermObligationsNoncurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermObligationsNoncurrent_lbl1" xml:lang="en-US" id="ions_LongTermObligationsNoncurrent_lbl1">Long-term Obligations, Noncurrent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsNoncurrent" xlink:to="ions_LongTermObligationsNoncurrent_lbl1" xlink:title="label: LongTermObligationsNoncurrent to ions_LongTermObligationsNoncurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsNoncurrent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LongTermObligationsNoncurrent_lbl2" xml:lang="en-US" id="ions_LongTermObligationsNoncurrent_lbl2">Long-term obligations, less current portion</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsNoncurrent" xlink:to="ions_LongTermObligationsNoncurrent_lbl2" xlink:title="label: LongTermObligationsNoncurrent to ions_LongTermObligationsNoncurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LongTermObligationsCurrent" xlink:label="LongTermObligationsCurrent" xlink:title="LongTermObligationsCurrent" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsCurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermObligationsCurrent_lbl" xml:lang="en-US" id="ions_LongTermObligationsCurrent_lbl">Amount of long-term obligations, including debt and capital leases, due within one year or 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="LongTermObligationsCurrent" xlink:to="ions_LongTermObligationsCurrent_lbl" xlink:title="label: LongTermObligationsCurrent to ions_LongTermObligationsCurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsCurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermObligationsCurrent_lbl1" xml:lang="en-US" id="ions_LongTermObligationsCurrent_lbl1">Long-term Obligations, Current</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsCurrent" xlink:to="ions_LongTermObligationsCurrent_lbl1" xlink:title="label: LongTermObligationsCurrent to ions_LongTermObligationsCurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermObligationsCurrent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LongTermObligationsCurrent_lbl2" xml:lang="en-US" id="ions_LongTermObligationsCurrent_lbl2">Current portion of long-term obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermObligationsCurrent" xlink:to="ions_LongTermObligationsCurrent_lbl2" xlink:title="label: LongTermObligationsCurrent to ions_LongTermObligationsCurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LongTermFinancingObligationNoncurrent" xlink:label="LongTermFinancingObligationNoncurrent" xlink:title="LongTermFinancingObligationNoncurrent" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermFinancingObligationNoncurrent_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermFinancingObligationNoncurrent_lbl" xml:lang="en-US" id="ions_LongTermFinancingObligationNoncurrent_lbl">Long-term financing obligation related to a lease agreement with an affiliate of of BioMed Realty, L.P. for the construction of the company's primary research and development facility in Carlsbad, California due in the next twelve months or greater than the normal operating cycle, if longer. In order to gain early access to the facility, the company modified the lease to accept additional responsibility.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermFinancingObligationNoncurrent" xlink:to="ions_LongTermFinancingObligationNoncurrent_lbl" xlink:title="label: LongTermFinancingObligationNoncurrent to ions_LongTermFinancingObligationNoncurrent_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermFinancingObligationNoncurrent_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermFinancingObligationNoncurrent_lbl1" xml:lang="en-US" id="ions_LongTermFinancingObligationNoncurrent_lbl1">Long-term financing obligation, Noncurrent</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermFinancingObligationNoncurrent" xlink:to="ions_LongTermFinancingObligationNoncurrent_lbl1" xlink:title="label: LongTermFinancingObligationNoncurrent to ions_LongTermFinancingObligationNoncurrent_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermFinancingObligationNoncurrent_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LongTermFinancingObligationNoncurrent_lbl2" xml:lang="en-US" id="ions_LongTermFinancingObligationNoncurrent_lbl2">Long-term financing liability for leased facility</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermFinancingObligationNoncurrent" xlink:to="ions_LongTermFinancingObligationNoncurrent_lbl2" xlink:title="label: LongTermFinancingObligationNoncurrent to ions_LongTermFinancingObligationNoncurrent_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones" xlink:label="MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones" xlink:title="MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl">The maximum amount of payments payable for regulatory and commercialization milestones under the collaboration agreement.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones" xlink:to="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl" xlink:title="label: MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones to ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl1" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl1">Maximum amount of payments payable for regulatory and commercialization milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones" xlink:to="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl1" xlink:title="label: MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones to ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl2" xml:lang="en-US" id="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl2">Maximum amount of payments payable for regulatory and commercialization milestones</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones" xlink:to="ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl2" xlink:title="label: MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones to ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember" xlink:label="CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember" xlink:title="CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl">Represents information pertaining to the collaborative arrangement entered into with Cystic Fibrosis Foundation in August 2016 to discover and advance a drug for the treatment of Cystic Fibrosis.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl1" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl1">Collaborative Arrangement and Licensing Agreement Entered Into in August 2016 with Cystic Fibrosis Foundation [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl1" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl2" xml:lang="en-US" id="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl2">Cystic Fibrosis Foundation [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember" xlink:to="ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl2" xlink:title="label: CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember to ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.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-20181231.xsd#ions_AkceaTherapeuticsIncMember" xlink:label="AkceaTherapeuticsIncMember" xlink:title="AkceaTherapeuticsIncMember" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaTherapeuticsIncMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_AkceaTherapeuticsIncMember_lbl" xml:lang="en-US" id="ions_AkceaTherapeuticsIncMember_lbl">Akcea Therapeutics, Inc. is a subsidiary of the Company and was formed to develop and commercialize drugs for cardiometabolic disorders.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaTherapeuticsIncMember" xlink:to="ions_AkceaTherapeuticsIncMember_lbl" xlink:title="label: AkceaTherapeuticsIncMember to ions_AkceaTherapeuticsIncMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaTherapeuticsIncMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_AkceaTherapeuticsIncMember_lbl1" xml:lang="en-US" id="ions_AkceaTherapeuticsIncMember_lbl1">Akcea Therapeutics, Inc. [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaTherapeuticsIncMember" xlink:to="ions_AkceaTherapeuticsIncMember_lbl1" xlink:title="label: AkceaTherapeuticsIncMember to ions_AkceaTherapeuticsIncMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_AkceaTherapeuticsIncMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_AkceaTherapeuticsIncMember_lbl2" xml:lang="en-US" id="ions_AkceaTherapeuticsIncMember_lbl2">Akcea [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="AkceaTherapeuticsIncMember" xlink:to="ions_AkceaTherapeuticsIncMember_lbl2" xlink:title="label: AkceaTherapeuticsIncMember to ions_AkceaTherapeuticsIncMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug" xlink:label="SharesToBeReceivedFromSubsidiaryForLicenseOfDrug" xlink:title="SharesToBeReceivedFromSubsidiaryForLicenseOfDrug" />
    <link:label xlink:type="resource" xlink:label="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl" xml:lang="en-US" id="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl">The number of additional shares of stock to be received from Akcea Therapeutics, Inc. as a sublicense fee as result of Novartis licensing AKCEA-APO(a)-L.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SharesToBeReceivedFromSubsidiaryForLicenseOfDrug" xlink:to="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl" xlink:title="label: SharesToBeReceivedFromSubsidiaryForLicenseOfDrug to ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl1" xml:lang="en-US" id="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl1">Shares to be received from subsidiary for license of drug</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SharesToBeReceivedFromSubsidiaryForLicenseOfDrug" xlink:to="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl1" xlink:title="label: SharesToBeReceivedFromSubsidiaryForLicenseOfDrug to ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl2" xml:lang="en-US" id="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl2">Additional shares of Akcea stock to be received for license of AKCEA-APO(a)-L (in shares)</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SharesToBeReceivedFromSubsidiaryForLicenseOfDrug" xlink:to="ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl2" xlink:title="label: SharesToBeReceivedFromSubsidiaryForLicenseOfDrug to ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug" xlink:label="SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug" xlink:title="SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug" />
    <link:label xlink:type="resource" xlink:label="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl" xml:lang="en-US" id="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl">The amount of the sublicense fee to be paid in Akcea common stock as a result of Novartis licensing AKCEA-APO(a)-L.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug" xlink:to="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl" xlink:title="label: SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug to ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl1" xml:lang="en-US" id="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl1">Sublicense fee to be paid by subsidiary for license of drug</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug" xlink:to="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl1" xlink:title="label: SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug to ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl2" xml:lang="en-US" id="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl2">Sublicense fee to be paid in stock by Akcea for license of AKCEA-AP)(a)-L</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug" xlink:to="ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl2" xlink:title="label: SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug to ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ConvertibleSeniorNotes275PercentMember" xlink:label="ConvertibleSeniorNotes275PercentMember" xlink:title="ConvertibleSeniorNotes275PercentMember" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes275PercentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConvertibleSeniorNotes275PercentMember_lbl" xml:lang="en-US" id="ions_ConvertibleSeniorNotes275PercentMember_lbl">2 3/4 percent convertible senior notes due October 2019.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes275PercentMember" xlink:to="ions_ConvertibleSeniorNotes275PercentMember_lbl" xlink:title="label: ConvertibleSeniorNotes275PercentMember to ions_ConvertibleSeniorNotes275PercentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes275PercentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConvertibleSeniorNotes275PercentMember_lbl1" xml:lang="en-US" id="ions_ConvertibleSeniorNotes275PercentMember_lbl1">Convertible Senior Notes 2.75 Percent [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes275PercentMember" xlink:to="ions_ConvertibleSeniorNotes275PercentMember_lbl1" xlink:title="label: ConvertibleSeniorNotes275PercentMember to ions_ConvertibleSeniorNotes275PercentMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes275PercentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ConvertibleSeniorNotes275PercentMember_lbl2" xml:lang="en-US" id="ions_ConvertibleSeniorNotes275PercentMember_lbl2">2 3/4 Percent Convertible Senior Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes275PercentMember" xlink:to="ions_ConvertibleSeniorNotes275PercentMember_lbl2" xlink:title="label: ConvertibleSeniorNotes275PercentMember to ions_ConvertibleSeniorNotes275PercentMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_MorganStanleyPrivateBankNationalAssociationMember" xlink:label="MorganStanleyPrivateBankNationalAssociationMember" xlink:title="MorganStanleyPrivateBankNationalAssociationMember" />
    <link:label xlink:type="resource" xlink:label="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl" xml:lang="en-US" id="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl">Morgan Stanley Private Bank, National Association offers banking and credit products and services. The company was founded in 1996 and is based in Purchase, New York. Morgan Stanley Private Bank, National Association operates as a subsidiary of Morgan Stanley.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MorganStanleyPrivateBankNationalAssociationMember" xlink:to="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl" xlink:title="label: MorganStanleyPrivateBankNationalAssociationMember to ions_MorganStanleyPrivateBankNationalAssociationMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl1" xml:lang="en-US" id="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl1">Morgan Stanley Private Bank, National Association [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MorganStanleyPrivateBankNationalAssociationMember" xlink:to="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl1" xlink:title="label: MorganStanleyPrivateBankNationalAssociationMember to ions_MorganStanleyPrivateBankNationalAssociationMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl2" xml:lang="en-US" id="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl2">Morgan Stanley [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="MorganStanleyPrivateBankNationalAssociationMember" xlink:to="ions_MorganStanleyPrivateBankNationalAssociationMember_lbl2" xlink:title="label: MorganStanleyPrivateBankNationalAssociationMember to ions_MorganStanleyPrivateBankNationalAssociationMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_TermOfVariableRate" xlink:label="TermOfVariableRate" xlink:title="TermOfVariableRate" />
    <link:label xlink:type="resource" xlink:label="ions_TermOfVariableRate_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_TermOfVariableRate_lbl" xml:lang="en-US" id="ions_TermOfVariableRate_lbl">Term of the variable rate.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TermOfVariableRate" xlink:to="ions_TermOfVariableRate_lbl" xlink:title="label: TermOfVariableRate to ions_TermOfVariableRate_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_TermOfVariableRate_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_TermOfVariableRate_lbl1" xml:lang="en-US" id="ions_TermOfVariableRate_lbl1">Term of variable rate</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="TermOfVariableRate" xlink:to="ions_TermOfVariableRate_lbl1" xlink:title="label: TermOfVariableRate to ions_TermOfVariableRate_lbl1" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_ConvertibleSeniorNotes1PercentMember" xlink:label="ConvertibleSeniorNotes1PercentMember" xlink:title="ConvertibleSeniorNotes1PercentMember" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes1PercentMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_ConvertibleSeniorNotes1PercentMember_lbl" xml:lang="en-US" id="ions_ConvertibleSeniorNotes1PercentMember_lbl">1 percent convertible senior notes due November 2021.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes1PercentMember" xlink:to="ions_ConvertibleSeniorNotes1PercentMember_lbl" xlink:title="label: ConvertibleSeniorNotes1PercentMember to ions_ConvertibleSeniorNotes1PercentMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes1PercentMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_ConvertibleSeniorNotes1PercentMember_lbl1" xml:lang="en-US" id="ions_ConvertibleSeniorNotes1PercentMember_lbl1">Convertible Senior Notes 1 Percent [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes1PercentMember" xlink:to="ions_ConvertibleSeniorNotes1PercentMember_lbl1" xlink:title="label: ConvertibleSeniorNotes1PercentMember to ions_ConvertibleSeniorNotes1PercentMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_ConvertibleSeniorNotes1PercentMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_ConvertibleSeniorNotes1PercentMember_lbl2" xml:lang="en-US" id="ions_ConvertibleSeniorNotes1PercentMember_lbl2">1 Percent Convertible Senior Notes [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="ConvertibleSeniorNotes1PercentMember" xlink:to="ions_ConvertibleSeniorNotes1PercentMember_lbl2" xlink:title="label: ConvertibleSeniorNotes1PercentMember to ions_ConvertibleSeniorNotes1PercentMember_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LongTermDebtAndOtherObligations" xlink:label="LongTermDebtAndOtherObligations" xlink:title="LongTermDebtAndOtherObligations" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermDebtAndOtherObligations_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermDebtAndOtherObligations_lbl" xml:lang="en-US" id="ions_LongTermDebtAndOtherObligations_lbl">Including the current and noncurrent portions, aggregate carrying value as of the balance sheet date of long-term debt, capital lease and other obligations (with maturities initially due after one year or beyond the operating cycle if longer).</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermDebtAndOtherObligations" xlink:to="ions_LongTermDebtAndOtherObligations_lbl" xlink:title="label: LongTermDebtAndOtherObligations to ions_LongTermDebtAndOtherObligations_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermDebtAndOtherObligations_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermDebtAndOtherObligations_lbl1" xml:lang="en-US" id="ions_LongTermDebtAndOtherObligations_lbl1">Long-term Debt and Other Obligations</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermDebtAndOtherObligations" xlink:to="ions_LongTermDebtAndOtherObligations_lbl1" xlink:title="label: LongTermDebtAndOtherObligations to ions_LongTermDebtAndOtherObligations_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermDebtAndOtherObligations_lbl2" xlink:role="http://www.xbrl.org/2003/role/totalLabel" xlink:title="ions_LongTermDebtAndOtherObligations_lbl2" xml:lang="en-US" id="ions_LongTermDebtAndOtherObligations_lbl2">Total long-term obligations, including current portion</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermDebtAndOtherObligations" xlink:to="ions_LongTermDebtAndOtherObligations_lbl2" xlink:title="label: LongTermDebtAndOtherObligations to ions_LongTermDebtAndOtherObligations_lbl2" />
    <link:loc xlink:type="locator" xlink:href="ions-20181231.xsd#ions_LongTermMortgageDebtMember" xlink:label="LongTermMortgageDebtMember" xlink:title="LongTermMortgageDebtMember" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermMortgageDebtMember_lbl" xlink:role="http://www.xbrl.org/2003/role/documentation" xlink:title="ions_LongTermMortgageDebtMember_lbl" xml:lang="en-US" id="ions_LongTermMortgageDebtMember_lbl">Two loan agreements with UBS AG entered into on July 18, 2017 to partially finance the purchase of the Company's research and development and manufacturing facilities.</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermMortgageDebtMember" xlink:to="ions_LongTermMortgageDebtMember_lbl" xlink:title="label: LongTermMortgageDebtMember to ions_LongTermMortgageDebtMember_lbl" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermMortgageDebtMember_lbl1" xlink:role="http://www.xbrl.org/2003/role/label" xlink:title="ions_LongTermMortgageDebtMember_lbl1" xml:lang="en-US" id="ions_LongTermMortgageDebtMember_lbl1">Long-term Mortgage Debt [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermMortgageDebtMember" xlink:to="ions_LongTermMortgageDebtMember_lbl1" xlink:title="label: LongTermMortgageDebtMember to ions_LongTermMortgageDebtMember_lbl1" />
    <link:label xlink:type="resource" xlink:label="ions_LongTermMortgageDebtMember_lbl2" xlink:role="http://www.xbrl.org/2003/role/terseLabel" xlink:title="ions_LongTermMortgageDebtMember_lbl2" xml:lang="en-US" id="ions_LongTermMortgageDebtMember_lbl2">Long-term Mortgage Debt [Member]</link:label>
    <link:labelArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/concept-label" xlink:from="LongTermMortgageDebtMember" xlink:to="ions_LongTermMortgageDebtMember_lbl2" xlink:title="label: LongTermMortgageDebtMember to ions_LongTermMortgageDebtMember_lbl2" />
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<DOCUMENT>
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<TEXT>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6819031616">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Document and Entity Information - USD ($)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Feb. 20, 2019</div></th>
<th class="th"><div>Jun. 30, 2018</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DocumentAndEntityInformationAbstract', window );"><strong>Document and Entity Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityRegistrantName', window );">Entity Registrant Name</a></td>
<td class="text">IONIS PHARMACEUTICALS INC<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityCentralIndexKey', window );">Entity Central Index Key</a></td>
<td class="text">0000874015<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_CurrentFiscalYearEndDate', window );">Current Fiscal Year End Date</a></td>
<td class="text">--12-31<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityWellKnownSeasonedIssuer', window );">Entity Well-known Seasoned Issuer</a></td>
<td class="text">Yes<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityVoluntaryFilers', window );">Entity Voluntary Filers</a></td>
<td class="text">No<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityCurrentReportingStatus', window );">Entity Current Reporting Status</a></td>
<td class="text">Yes<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityShellCompany', window );">Entity Shell Company</a></td>
<td class="text">false<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityFilerCategory', window );">Entity Filer Category</a></td>
<td class="text">Large Accelerated Filer<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntitySmallBusiness', window );">Entity Small Business</a></td>
<td class="text">false<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityEmergingGrowthCompany', window );">Entity Emerging Growth Company</a></td>
<td class="text">false<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityExTransitionPeriod', window );">Entity Ex Transition Period</a></td>
<td class="text">false<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityPublicFloat', window );">Entity Public Float</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="nump">$ 4,805,287,142<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_EntityCommonStockSharesOutstanding', window );">Entity Common Stock, Shares Outstanding</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">138,397,754<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentType', window );">Document Type</a></td>
<td class="text">10-K<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_AmendmentFlag', window );">Amendment Flag</a></td>
<td class="text">false<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentPeriodEndDate', window );">Document Period End Date</a></td>
<td class="text">Dec. 31,  2018<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentFiscalYearFocus', window );">Document Fiscal Year Focus</a></td>
<td class="text">2018<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_dei_DocumentFiscalPeriodFocus', window );">Document Fiscal Period Focus</a></td>
<td class="text">FY<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<div style="display: none;">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>If the value is true, then the document is an amendment to previously-filed/accepted document.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_AmendmentFlag</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>End date of current fiscal year in the format --MM-DD.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>This is focus fiscal period of the document report. For a first quarter 2006 quarterly report, which may also provide financial information from prior periods, the first fiscal quarter should be given as the fiscal period focus. Values: FY, Q1, Q2, Q3, Q4, H1, H2, M9, T1, T2, T3, M8, CY.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>This is focus fiscal year of the document report in CCYY format. For a 2006 annual report, which may also provide financial information from prior periods, fiscal 2006 should be given as the fiscal year focus. Example: 2006.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The end date of the period reflected on the cover page if a periodic report. For all other reports and registration statements containing historical data, it is the date up through which that historical data is presented.  If there is no historical data in the report, use the filing date. The format of the date is CCYY-MM-DD.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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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_DocumentType">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The type of document being provided (such as 10-K, 10-Q, 485BPOS, etc). The document type is limited to the same value as the supporting SEC submission type, or the word 'Other'.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_DocumentType</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:submissionTypeItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityCentralIndexKey">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A unique 10-digit SEC-issued value to identify entities that have filed disclosures with the SEC. It is commonly abbreviated as CIK.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation 12B<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityCentralIndexKey</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:centralIndexKeyItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityCommonStockSharesOutstanding">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate number of shares or other units outstanding of each of registrant's classes of capital or common stock or other ownership interests, if and as stated on cover of related periodic report. Where multiple classes or units exist define each class/interest by adding class of stock items such as Common Class A [Member], Common Class B [Member] or Partnership Interest [Member] onto the Instrument [Domain] of the Entity Listings, Instrument.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityCommonStockSharesOutstanding</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityCurrentReportingStatus">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate 'Yes' or 'No' whether registrants (1) have filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that registrants were required to file such reports), and (2) have been subject to such filing requirements for the past 90 days. This information should be based on the registrant's current or most recent filing containing the related disclosure.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityCurrentReportingStatus</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:yesNoItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityEmergingGrowthCompany">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate if registrant meets the emerging growth company criteria.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation 12B<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityEmergingGrowthCompany</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityExTransitionPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate if registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 7A<br> -Section B<br> -Subsection 2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityExTransitionPeriod</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_EntityFilerCategory">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate whether the registrant is one of the following: (1) Large Accelerated Filer, (2) Accelerated Filer, (3) Non-accelerated Filer, (4) Smaller Reporting Company (Non-accelerated), (5) Smaller Reporting Accelerated Filer or (6) Smaller Reporting Company and Large Accelerated Filer. Definitions of these categories are stated in Rule 12b-2 of the Exchange Act. This information should be based on the registrant's current or most recent filing containing the related disclosure.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation 12B<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityFilerCategory</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:filerCategoryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityPublicFloat">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>State aggregate market value of voting and non-voting common equity held by non-affiliates computed by reference to price at which the common equity was last sold, or average bid and asked price of such common equity, as of the last business day of registrant's most recently completed second fiscal quarter. The public float should be reported on the cover page of the registrants form 10K.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityPublicFloat</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityRegistrantName">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The exact name of the entity filing the report as specified in its charter, which is required by forms filed with the SEC.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation 12B<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityRegistrantName</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:normalizedStringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityShellCompany">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate if company meets the shell company criteria: a company with no or nominal operations, and with no or nominal assets or assets consisting solely of cash and cash equivalents.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation 12B<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityShellCompany</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntitySmallBusiness">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicates that the company is a smaller reporting company with both a public float and revenues of less than $75 million.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Regulation 12B<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntitySmallBusiness</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:booleanItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityVoluntaryFilers">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate 'Yes' or 'No' if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityVoluntaryFilers</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:yesNoItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_dei_EntityWellKnownSeasonedIssuer">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Indicate 'Yes' or 'No' if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Is used on Form Type: 10-K, 10-Q, 8-K, 20-F, 6-K, 10-K/A, 10-Q/A, 20-F/A, 6-K/A, N-CSR, N-Q, N-1A.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityWellKnownSeasonedIssuer</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>dei_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>dei:yesNoItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DocumentAndEntityInformationAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DocumentAndEntityInformationAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONSOLIDATED BALANCE SHEETS - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
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</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents</a></td>
<td class="nump">$ 278,820<span></span>
</td>
<td class="nump">$ 129,630<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent', window );">Short-term investments</a></td>
<td class="nump">1,805,252<span></span>
</td>
<td class="nump">893,085<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerAssetNetCurrent', window );">Contracts receivable</a></td>
<td class="nump">12,759<span></span>
</td>
<td class="nump">62,955<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryNet', window );">Inventories</a></td>
<td class="nump">8,582<span></span>
</td>
<td class="nump">9,982<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherAssetsCurrent', window );">Other current assets</a></td>
<td class="nump">102,473<span></span>
</td>
<td class="nump">73,082<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsCurrent', window );">Total current assets</a></td>
<td class="nump">2,207,886<span></span>
</td>
<td class="nump">1,168,734<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentNet', window );">Property, plant and equipment, net</a></td>
<td class="nump">132,160<span></span>
</td>
<td class="nump">121,907<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsNet', window );">Patents, net</a></td>
<td class="nump">24,032<span></span>
</td>
<td class="nump">22,004<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsLiabilitiesNetNoncurrent', window );">Long-term deferred tax assets</a></td>
<td class="nump">290,796<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherAssetsNoncurrent', window );">Deposits and other assets</a></td>
<td class="nump">12,910<span></span>
</td>
<td class="nump">10,129<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Assets', window );">Total assets</a></td>
<td class="nump">2,667,784<span></span>
</td>
<td class="nump">1,322,774<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesCurrentAbstract', window );"><strong>Current liabilities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccountsPayableCurrent', window );">Accounts payable</a></td>
<td class="nump">28,660<span></span>
</td>
<td class="nump">24,886<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeRelatedLiabilitiesCurrent', window );">Accrued compensation</a></td>
<td class="nump">29,268<span></span>
</td>
<td class="nump">25,151<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccruedLiabilitiesCurrent', window );">Accrued liabilities</a></td>
<td class="nump">48,361<span></span>
</td>
<td class="nump">66,618<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermObligationsCurrent', window );">Current portion of long-term obligations</a></td>
<td class="nump">13,749<span></span>
</td>
<td class="nump">1,621<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityCurrent', window );">Current portion of deferred contract revenue</a></td>
<td class="nump">160,256<span></span>
</td>
<td class="nump">125,336<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesCurrent', window );">Total current liabilities</a></td>
<td class="nump">280,294<span></span>
</td>
<td class="nump">243,612<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityNoncurrent', window );">Long-term deferred contract revenue</a></td>
<td class="nump">567,359<span></span>
</td>
<td class="nump">108,026<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">1 percent convertible senior notes</a></td>
<td class="nump">568,215<span></span>
</td>
<td class="nump">533,111<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermObligationsNoncurrent', window );">Long-term obligations, less current portion</a></td>
<td class="nump">4,914<span></span>
</td>
<td class="nump">12,974<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermLoansFromBank', window );">Long-term mortgage debt</a></td>
<td class="nump">59,842<span></span>
</td>
<td class="nump">59,771<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Liabilities', window );">Total liabilities</a></td>
<td class="nump">1,480,624<span></span>
</td>
<td class="nump">957,494<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityAbstract', window );"><strong>Stockholders' equity:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockValue', window );">Common stock, $0.001 par value; 300,000,000 shares authorized, 137,928,828 and 124,976,373 shares issued and outstanding at December 31, 2018 and December 31, 2017, respectively</a></td>
<td class="nump">138<span></span>
</td>
<td class="nump">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="top.Show.showAR( this, 'defref_us-gaap_AdditionalPaidInCapitalCommonStock', window );">Additional paid-in capital</a></td>
<td class="nump">2,047,250<span></span>
</td>
<td class="nump">1,553,681<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax', window );">Accumulated other comprehensive loss</a></td>
<td class="num">(32,016)<span></span>
</td>
<td class="num">(31,759)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RetainedEarningsAccumulatedDeficit', window );">Accumulated deficit</a></td>
<td class="num">(967,293)<span></span>
</td>
<td class="num">(1,241,034)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquity', window );">Total Ionis stockholders' equity</a></td>
<td class="nump">1,048,079<span></span>
</td>
<td class="nump">281,013<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterest', window );">Noncontrolling interest in Akcea Therapeutics, Inc.</a></td>
<td class="nump">139,081<span></span>
</td>
<td class="nump">84,267<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Total stockholders' equity</a></td>
<td class="nump">1,187,160<span></span>
</td>
<td class="nump">365,280<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesAndStockholdersEquity', window );">Total liabilities and stockholders' equity</a></td>
<td class="nump">$ 2,667,784<span></span>
</td>
<td class="nump">$ 1,322,774<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LongTermObligationsCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term obligations, including debt and capital leases, due within one year or the normal operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LongTermObligationsCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LongTermObligationsNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying amount of long-term obligations due in the next twelve months or greater than the normal operating cycle, if longer, excluding convertible senior notes and a long-term financing liability for a leased facility.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LongTermObligationsNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccountsPayableCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of liabilities incurred (and for which invoices have typically been received) and payable to vendors for goods and services received that are used in an entity's business. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.19(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccountsPayableCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccruedLiabilitiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of obligations incurred and payable, pertaining to costs that are statutory in nature, are incurred on contractual obligations, or accumulate over time and for which invoices have not yet been received or will not be rendered. Examples include taxes, interest, rent and utilities. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.20)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccruedLiabilitiesCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Accumulated change in equity from transactions and other events and circumstances from non-owner sources, net of tax effect, at period end. Excludes Net Income (Loss), and accumulated changes in equity from transactions resulting from investments by owners and distributions to owners. Includes foreign currency translation items, certain pension adjustments, unrealized gains and losses on certain investments in debt and equity securities, other than temporary impairment (OTTI) losses related to factors other than credit losses on available-for-sale and held-to-maturity debt securities that an entity does not intend to sell and it is not more likely than not that the entity will be required to sell before recovery of the amortized cost basis, as well as changes in the fair value of derivatives related to the effective portion of a designated cash flow hedge.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=d3e637-108580<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14A<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669686-108580<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 14<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=d3e681-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Value received from shareholders in common stock-related transactions that are in excess of par value or stated value and amounts received from other stock-related transactions. Includes only common stock transactions (excludes preferred stock transactions). May be called contributed capital, capital in excess of par, capital surplus, or paid-in capital.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(30)(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdditionalPaidInCapitalCommonStock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_Assets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Sum of the carrying amounts as of the balance sheet date of all assets that are recognized. Assets are probable future economic benefits obtained or controlled by an entity as a result of past transactions or events.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(11))<br> -URI http://asc.fasb.org/extlink&amp;oid=6876686&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 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<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)(12))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&amp;loc=d3e572229-122910<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Sum of the carrying amounts as of the balance sheet date of all assets that are 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="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=82887183&amp;loc=d3e6801-107765<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 210.5-02.9)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&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 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82887183&amp;loc=d3e6676-107765<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AssetsCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AssetsCurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AssetsCurrentAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<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_AvailableForSaleSecuritiesDebtSecuritiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale), classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109979856&amp;loc=d3e26626-111562<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesDebtSecuritiesCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CashAndCashEquivalentsAtCarryingValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of currency on hand as well as demand deposits with banks or financial institutions. Includes other kinds of accounts that have the general characteristics of demand deposits. Also includes short-term, highly liquid investments that are both readily convertible to known amounts of cash and so near their maturity that they present insignificant risk of changes in value because of changes in interest rates. Excludes cash and cash equivalents within disposal group and discontinued operation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3044-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=82887183&amp;loc=d3e6676-107765<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.1)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashAndCashEquivalentsAtCarryingValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CommonStockValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Aggregate par or stated value of issued nonredeemable common stock (or common stock redeemable solely at the option of the issuer). This item includes treasury stock repurchased by the entity. Note: elements for number of nonredeemable common shares, par value and other disclosure concepts are in another section within stockholders' equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerAssetNetCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after allowance for credit loss, of right to consideration in exchange for good or service transferred to customer when right is conditioned on something other than passage of time, classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130533-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerAssetNetCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiabilityCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable, classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiabilityCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiabilityNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable, classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying amount of long-term convertible debt as of the balance sheet date, net of the amount due in the next twelve months or greater than the normal operating cycle, if longer. The debt is convertible into another form of financial instrument, typically the entity's common stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConvertibleDebtNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsLiabilitiesNetNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after allocation of valuation allowances and deferred tax liability, of deferred tax asset attributable to deductible differences and carryforwards, with jurisdictional netting and classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=84176650&amp;loc=d3e31917-109318<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=84176650&amp;loc=d3e31931-109318<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32537-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsLiabilitiesNetNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_EmployeeRelatedLiabilitiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total of the carrying values as of the balance sheet date of obligations incurred through that date and payable for obligations related to services received from employees, such as accrued salaries and bonuses, payroll taxes and fringe benefits. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.20)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeRelatedLiabilitiesCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_FiniteLivedIntangibleAssetsNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after amortization of assets, excluding financial assets and goodwill, lacking physical substance with a finite life.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_InventoryNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after valuation and LIFO reserves of inventory expected to be sold, or consumed within one year or operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=82887183&amp;loc=d3e6676-107765<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -SubTopic 10<br> -Section 35<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=68049868&amp;loc=d3e3927-108312<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.6(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InventoryNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_Liabilities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Sum of the carrying amounts as of the balance sheet date of all liabilities that are recognized. Liabilities are probable future sacrifices of economic benefits arising from present obligations of an entity to transfer assets or provide services to other entities in the future.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.19-26)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_Liabilities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LiabilitiesAndStockholdersEquity">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of liabilities and equity items, including the portion of equity attributable to noncontrolling interests, if any.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=6876686&amp;loc=d3e534808-122878<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(25))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&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(32))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LiabilitiesAndStockholdersEquity</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LiabilitiesCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total obligations incurred as part of normal operations that are expected to be paid during the following twelve months or within one business cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.21)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LiabilitiesCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LiabilitiesCurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LiabilitiesCurrentAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of loans from a bank with maturities initially due after one year or beyond the operating cycle if longer, excluding current portion.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=6876686&amp;loc=d3e534808-122878<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(16)(a)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&amp;loc=d3e572229-122910<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LongTermLoansFromBank</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_MinorityInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total of all stockholders' equity (deficit) items, net of receivables from officers, directors, owners, and affiliates of the entity which is directly or indirectly attributable to that ownership interest in subsidiary equity which is not attributable to the parent (that is, noncontrolling interest, previously referred to as minority interest).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(24))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&amp;loc=d3e572229-122910<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.31)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=6876686&amp;loc=d3e534808-122878<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MinorityInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherAssetsCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current assets classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.8)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherAssetsCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherAssetsNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of noncurrent assets classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.17)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherAssetsNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after accumulated depreciation, depletion and amortization of physical assets used in the normal conduct of business to produce goods and services and not intended for resale. Examples include, but are not limited to, land, buildings, machinery and equipment, office equipment, and furniture and fixtures.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(14))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(8))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&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 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(13))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RetainedEarningsAccumulatedDeficit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cumulative amount of the reporting entity's undistributed earnings or deficit.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(30)(a)(3))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(23)(a)(4))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&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 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=27012166&amp;loc=d3e187085-122770<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RetainedEarningsAccumulatedDeficit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquity">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total of all stockholders' equity (deficit) items, net of receivables from officers, directors, owners, and affiliates of the entity which are attributable to the parent. The amount of the economic entity's stockholders' equity attributable to the parent excludes the amount of stockholders' equity which is allocable to that ownership interest in subsidiary equity which is not attributable to the parent (noncontrolling interest, minority interest). This excludes temporary equity and is sometimes called permanent equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 310<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SAB Topic 4.E)<br> -URI http://asc.fasb.org/extlink&amp;oid=27010918&amp;loc=d3e74512-122707<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(31))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&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 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&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(30))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquity</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
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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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquityAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of stockholders' equity (deficit), net of receivables from officers, directors, owners, and affiliates of the entity, attributable to both the parent and noncontrolling interests. Amount excludes temporary equity. Alternate caption for the concept is permanent equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4568740-111683<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4I<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4590271-111686<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 15<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4568447-111683<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6800031904">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONSOLIDATED BALANCE SHEETS (Parenthetical) - $ / shares<br></strong></div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityAbstract', window );"><strong>Stockholders' equity:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockParOrStatedValuePerShare', window );">Common stock, par value (in dollars per share)</a></td>
<td class="nump">$ 0.001<span></span>
</td>
<td class="nump">$ 0.001<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesAuthorized', window );">Common stock, shares authorized (in shares)</a></td>
<td class="nump">300,000,000<span></span>
</td>
<td class="nump">300,000,000<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesIssued', window );">Common stock, shares issued (in shares)</a></td>
<td class="nump">137,928,828<span></span>
</td>
<td class="nump">124,976,373<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesOutstanding', window );">Common stock, shares outstanding (in shares)</a></td>
<td class="nump">137,928,828<span></span>
</td>
<td class="nump">124,976,373<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LiabilitiesAndStockholdersEquityAbstract', window );"><strong>LIABILITIES AND STOCKHOLDERS' EQUITY</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</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_CommonStockParOrStatedValuePerShare">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Face amount or stated value per share of common stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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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<tr>
<td><strong> Data Type:</strong></td>
<td>num: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>
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</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CommonStockSharesAuthorized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum number of common shares permitted to be issued by an entity's charter and bylaws.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockSharesAuthorized</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
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<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>instant</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CommonStockSharesIssued">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total number of common shares of an entity that have been sold or granted to shareholders (includes common shares that were issued, repurchased and remain in the treasury). These shares represent capital invested by the firm's shareholders and owners, and may be all or only a portion of the number of shares authorized. Shares issued include shares outstanding and shares held in the treasury.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockSharesIssued</td>
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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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<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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares of common stock outstanding. Common stock represent the ownership interest in a corporation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockSharesOutstanding</td>
</tr>
<tr>
<td style="padding-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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LiabilitiesAndStockholdersEquityAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquityAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquityAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<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_ConvertibleSeniorNotes1PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</table></div>
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<head>
<title></title>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6820136288">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF OPERATIONS - USD ($)<br> shares in Thousands, $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 599,674<span></span>
</td>
<td class="nump">$ 514,179<span></span>
</td>
<td class="nump">$ 372,776<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingExpensesAbstract', window );"><strong>Expenses:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CostOfGoodsAndServicesSold', window );">Cost of products sold</a></td>
<td class="nump">1,820<span></span>
</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="top.Show.showAR( this, 'defref_ions_ResearchDevelopmentAndPatentExpense', window );">Research, development and patent</a></td>
<td class="nump">414,604<span></span>
</td>
<td class="nump">374,644<span></span>
</td>
<td class="nump">344,320<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SellingGeneralAndAdministrativeExpense', window );">Selling, general and administrative</a></td>
<td class="nump">244,622<span></span>
</td>
<td class="nump">108,488<span></span>
</td>
<td class="nump">48,616<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingExpenses', window );">Total operating expenses</a></td>
<td class="nump">661,046<span></span>
</td>
<td class="nump">483,132<span></span>
</td>
<td class="nump">392,936<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="num">(61,372)<span></span>
</td>
<td class="nump">31,047<span></span>
</td>
<td class="num">(20,160)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NonoperatingIncomeExpenseAbstract', window );"><strong>Other income (expense):</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentIncomeNet', window );">Investment income</a></td>
<td class="nump">30,187<span></span>
</td>
<td class="nump">8,179<span></span>
</td>
<td class="nump">5,472<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InterestExpense', window );">Interest expense</a></td>
<td class="num">(44,789)<span></span>
</td>
<td class="num">(44,752)<span></span>
</td>
<td class="num">(38,795)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_GainLossOnExtinguishmentOfFinancingLiability', window );">Loss on extinguishment of financing liability for leased facility</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(7,689)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(3,983)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherNonoperatingIncomeExpense', window );">Other expenses</a></td>
<td class="num">(182)<span></span>
</td>
<td class="num">(3,548)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments', window );">Loss before income tax benefit (expense)</a></td>
<td class="num">(76,156)<span></span>
</td>
<td class="num">(16,763)<span></span>
</td>
<td class="num">(57,466)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Income tax benefit (expense)</a></td>
<td class="nump">291,141<span></span>
</td>
<td class="nump">5,980<span></span>
</td>
<td class="num">(2,934)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="nump">214,985<span></span>
</td>
<td class="num">(10,783)<span></span>
</td>
<td class="num">(60,400)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAttributableToNoncontrollingInterest', window );">Net loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.</a></td>
<td class="nump">58,756<span></span>
</td>
<td class="nump">11,129<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="nump">$ 273,741<span></span>
</td>
<td class="nump">$ 346<span></span>
</td>
<td class="num">$ (60,400)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="nump">$ 2.09<span></span>
</td>
<td class="nump">$ 0.15<span></span>
</td>
<td class="num">$ (0.50)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic', window );">Shares used in computing basic net income (loss) per share (in shares)</a></td>
<td class="nump">132,320<span></span>
</td>
<td class="nump">124,016<span></span>
</td>
<td class="nump">120,933<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDiluted', window );">Diluted net income (loss) per share (in dollars per share)</a></td>
<td class="nump">$ 2.07<span></span>
</td>
<td class="nump">$ 0.15<span></span>
</td>
<td class="num">$ (0.50)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding', window );">Shares used in computing diluted net income (loss) per share (in shares)</a></td>
<td class="nump">134,056<span></span>
</td>
<td class="nump">126,098<span></span>
</td>
<td class="nump">120,933<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_CommercialMember', window );">Commercial Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 254,922<span></span>
</td>
<td class="nump">$ 120,014<span></span>
</td>
<td class="nump">$ 22,767<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_SPINRAZARoyaltiesMember', window );">SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">237,930<span></span>
</td>
<td class="nump">112,540<span></span>
</td>
<td class="nump">883<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=us-gaap_ProductMember', window );">TEGSEDI Product Sales, Net [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">2,237<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember', window );">Licensing and Other Royalty Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">14,755<span></span>
</td>
<td class="nump">7,474<span></span>
</td>
<td class="nump">21,884<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">Research and Development Revenue Under Collaborative Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenuesAbstract', window );"><strong>Revenue:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 344,752<span></span>
</td>
<td class="nump">$ 394,165<span></span>
</td>
<td class="nump">$ 350,009<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_GainLossOnExtinguishmentOfFinancingLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Difference between the purchase price of the facility and the carrying value of our financing liability at the time of the purchase.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_GainLossOnExtinguishmentOfFinancingLiability</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_ResearchDevelopmentAndPatentExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate costs incurred (1) in a planned search or critical investigation aimed at discovery of new knowledge with the hope that such knowledge will be useful in developing a new product or service, a new process or technique, or in bringing about a significant improvement to an existing product or process; or (2) to translate research findings or other knowledge into a plan or design for a new product or process or for a significant improvement to an existing product or process whether intended for sale or the entity's use, during the reporting period charged to research and development projects. Also includes charges for amortization and write-downs of capitalized patent costs, as well as legal fees for patent litigation and patent defense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate costs related to goods produced and sold and services rendered by an entity during the reporting period. This excludes costs incurred during the reporting period related to financial services rendered and other revenue generating activities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.2(a),(d))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period per each share of common stock or unit outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(19))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&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 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1337-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=109256448&amp;loc=d3e4984-109258<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 (SX 210.5-03(21))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<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> -URI http://asc.fasb.org/extlink&amp;oid=109234566&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 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1252-109256<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&amp;loc=SL114874048-224260<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=SL5780133-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>num:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareDiluted">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period available to each share of common stock or common unit outstanding during the reporting period and to each share or unit that would have been outstanding assuming the issuance of common shares or units for all dilutive potential common shares or units outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=109256448&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 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1252-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<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(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&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 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109234566&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 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1337-109256<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(21))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&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 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(19))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&amp;loc=SL114874131-224263<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>num:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GainsLossesOnExtinguishmentOfDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Difference between the fair value of payments made and the carrying amount of debt which is extinguished prior to maturity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=114001942&amp;loc=d3e12355-112629<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=114001942&amp;loc=d3e12317-112629<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainsLossesOnExtinguishmentOfDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of income (loss) from continuing operations before deduction of income tax expense (benefit) and income (loss) attributable to noncontrolling interest, and addition of income (loss) from equity method investments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08.(h)(1)(i))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current income tax expense (benefit) and deferred income tax expense (benefit) pertaining to continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (h)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109238882&amp;loc=d3e38679-109324<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InterestExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the cost of borrowed funds accounted for as interest expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6450988&amp;loc=d3e26243-108391<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&amp;loc=d3e28555-108399<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (210.5-03(11))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04.9)<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&amp;loc=SL114874048-224260<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InterestExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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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_InvestmentIncomeNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after accretion (amortization) of discount (premium), and investment expense, of interest income and dividend income on nonoperating securities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.9)<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&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 210.5-03.7(a),(b))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&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 S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.8)<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentIncomeNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of profit or loss for the period, net of income taxes, which is attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<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 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&amp;loc=SL114874048-224260<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<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 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(18))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&amp;loc=SL114874131-224263<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 S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(20))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br><br>Reference 7: 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> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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_NetIncomeLossAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of Net Income (Loss) attributable to noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (a)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4J<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591551-111686<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAttributableToNoncontrollingInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_NonoperatingIncomeExpenseAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingExpenses">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Generally recurring costs associated with normal operations except for the portion of these expenses which can be clearly related to production and included in cost of sales or services. Includes selling, general and administrative expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingExpenses</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingExpensesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingExpensesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The net result for the period of deducting operating expenses from operating revenues.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><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>
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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>
<td>duration</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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of income (expense) related to nonoperating activities, classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.9)<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherNonoperatingIncomeExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProfitLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (c)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4J<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591551-111686<br><br>Reference 7: 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 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3000-108585<br><br>Reference 8: 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 19<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4569616-111683<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8933-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4K<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591552-111686<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProfitLoss</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate total costs related to selling a firm's product and services, as well as all other general and administrative expenses. Direct selling expenses (for example, credit, warranty, and advertising) are expenses that can be directly linked to the sale of specific products. Indirect selling expenses are expenses that cannot be directly linked to the sale of specific products, for example telephone expenses, Internet, and postal charges. General and administrative expenses include salaries of non-sales personnel, rent, utilities, communication, etc.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -SubTopic 10<br> -Section 30<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=68048583&amp;loc=d3e3636-108311<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 210.5-03.4)<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SellingGeneralAndAdministrativeExpense</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The average number of shares or units issued and outstanding that are used in calculating diluted EPS or earnings per unit (EPU), determined based on the timing of issuance of shares or units in the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&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 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1505-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of [basic] shares or units, after adjustment for contingently issuable shares or units and other shares or units not deemed outstanding, determined by relating the portion of time within a reporting period that common shares or units have been outstanding to the total time in that period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1448-109256<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF COMPREHENSIVE INCOME (LOSS) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
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<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
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<tr class="re">
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<td class="num">$ (10,783)<span></span>
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<td class="num">$ (60,400)<span></span>
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<td class="num">(280)<span></span>
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<td class="num">(960)<span></span>
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<td class="num">(17,219)<span></span>
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<td class="nump">0<span></span>
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<td class="num">(374)<span></span>
</td>
<td class="nump">447<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax', window );">Currency translation adjustment</a></td>
<td class="nump">23<span></span>
</td>
<td class="num">(67)<span></span>
</td>
<td class="num">(21)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ComprehensiveIncomeNetOfTaxIncludingPortionAttributableToNoncontrollingInterest', window );">Comprehensive income (loss)</a></td>
<td class="nump">214,728<span></span>
</td>
<td class="num">(12,184)<span></span>
</td>
<td class="num">(77,193)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest', window );">Comprehensive loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.</a></td>
<td class="num">(58,781)<span></span>
</td>
<td class="num">(11,224)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ComprehensiveIncomeNetOfTax', window );">Comprehensive income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="nump">$ 273,509<span></span>
</td>
<td class="num">$ (960)<span></span>
</td>
<td class="num">$ (77,193)<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_ComprehensiveIncomeNetOfTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income and other comprehensive income, 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="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=d3e557-108580<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ComprehensiveIncomeNetOfTax</td>
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<tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income (loss) and other comprehensive income (loss), attributable to noncontrolling interests. Excludes changes in equity resulting from investments by owners and distributions to owners.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4K<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591552-111686<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 21<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4613674-111683<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4569643-111683<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ComprehensiveIncomeNetOfTaxIncludingPortionAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income and other comprehensive income. Excludes changes in equity resulting from investments by owners and distributions to owners.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4K<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591552-111686<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<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 19<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4569616-111683<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ComprehensiveIncomeNetOfTaxIncludingPortionAttributableToNoncontrollingInterest</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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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax, before reclassification adjustments of gain (loss) on foreign currency translation adjustments, foreign currency transactions designated and effective as economic hedges of a net investment in a foreign entity and intra-entity foreign currency transactions that are of a long-term-investment nature.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6450520&amp;loc=d3e32583-110901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=109240241&amp;loc=d3e32157-110900<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=109240241&amp;loc=d3e32211-110900<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=109240241&amp;loc=d3e32022-110900<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 10A<br> -Subparagraph (a-c)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669646-108580<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 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=d3e637-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax of reclassification adjustment from accumulated other comprehensive income for unrealized gain (loss) realized upon the sale of available-for-sale securities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=d3e689-108580<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=d3e637-108580<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 50<br> -Paragraph 9<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=82897076&amp;loc=d3e27357-111563<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 17A<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL34724391-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeLossReclassificationAdjustmentFromAOCIForSaleOfSecuritiesNetOfTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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</tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherComprehensiveIncomeUnrealizedHoldingGainLossOnSecuritiesArisingDuringPeriodNetOfTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax, before reclassification adjustments, of unrealized holding gain (loss) on available-for-sale securities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10A<br> -Subparagraph (e)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669646-108580<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=d3e637-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeUnrealizedHoldingGainLossOnSecuritiesArisingDuringPeriodNetOfTax</td>
</tr>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (c)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4J<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591551-111686<br><br>Reference 7: 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 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3000-108585<br><br>Reference 8: 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 19<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4569616-111683<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8933-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4K<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591552-111686<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProfitLoss</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>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">
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<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>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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</TEXT>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6824068048">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF STOCKHOLDERS' EQUITY - USD ($)<br> shares in Thousands, $ in Thousands</strong></div></th>
<th class="th"><div>Common Stock [Member]</div></th>
<th class="th">
<div>Common Stock [Member] </div>
<div>Novartis [Member]</div>
</th>
<th class="th">
<div>Common Stock [Member] </div>
<div>Biogen Inc. [Member]</div>
</th>
<th class="th"><div>Additional Paid In Capital [Member]</div></th>
<th class="th">
<div>Additional Paid In Capital [Member] </div>
<div>Novartis [Member]</div>
</th>
<th class="th">
<div>Additional Paid In Capital [Member] </div>
<div>Biogen Inc. [Member]</div>
</th>
<th class="th"><div>Accumulated Other Comprehensive Loss [Member]</div></th>
<th class="th">
<div>Accumulated Other Comprehensive Loss [Member] </div>
<div>Novartis [Member]</div>
</th>
<th class="th">
<div>Accumulated Other Comprehensive Loss [Member] </div>
<div>Biogen Inc. [Member]</div>
</th>
<th class="th"><div>Accumulated Deficit [Member]</div></th>
<th class="th">
<div>Accumulated Deficit [Member] </div>
<div>Novartis [Member]</div>
</th>
<th class="th">
<div>Accumulated Deficit [Member] </div>
<div>Biogen Inc. [Member]</div>
</th>
<th class="th"><div>Total Ionis Stockholders' Equity [Member]</div></th>
<th class="th">
<div>Total Ionis Stockholders' Equity [Member] </div>
<div>Novartis [Member]</div>
</th>
<th class="th">
<div>Total Ionis Stockholders' Equity [Member] </div>
<div>Biogen Inc. [Member]</div>
</th>
<th class="th"><div>Noncontrolling Interest in Akcea Therapeutics, Inc. [Member]</div></th>
<th class="th">
<div>Noncontrolling Interest in Akcea Therapeutics, Inc. [Member] </div>
<div>Novartis [Member]</div>
</th>
<th class="th">
<div>Noncontrolling Interest in Akcea Therapeutics, Inc. [Member] </div>
<div>Biogen Inc. [Member]</div>
</th>
<th class="th"><div>Total</div></th>
<th class="th"><div>Novartis [Member]</div></th>
<th class="th"><div>Biogen Inc. [Member]</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward', window );"><strong>Increase (Decrease) in Stockholders' Equity [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CumulativeEffectOfNewAccountingPrincipleInPeriodOfAdoption', window );">Cumulative adjustment related to adopting Topic 606 revenue recognition guidance | Topic 606 [Member]</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (86,108)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (86,108)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (86,108)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Dec. 31, 2015</a></td>
<td class="nump">$ 120<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,309,107<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(13,565)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,094,872)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">200,790<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">200,790<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Dec. 31, 2015</a></td>
<td class="nump">120,351<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward', window );"><strong>Increase (Decrease) in Stockholders' Equity [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss)</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(60,400)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(60,400)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(60,400)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent', window );">Change in unrealized gains (losses), net of tax</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(16,772)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(16,772)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(16,772)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax', window );">Foreign currency translation</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(21)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(21)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(21)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross', window );">Issuance of common stock in connection with employee stock plans</a></td>
<td class="nump">$ 2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">13,706<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">13,708<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">13,708<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation', window );">Issuance of common stock in connection with employee stock plans (in shares)</a></td>
<td class="nump">1,285<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption', window );">2 3/4 percent convertible senior notes redemption, equity portion</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(128,888)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(128,888)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(128,888)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebt', window );">1 percent convertible senior notes, equity portion, net of issuance costs</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">43,335<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">43,335<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">43,335<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue', window );">Stock-based compensation expense</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">72,108<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">72,108<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">72,108<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest', window );">Noncontrolling interest in Akcea Therapetuics, Inc.</a></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalTaxEffectFromShareBasedCompensation', window );">Excess tax benefits from stock-based compensation awards</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,861<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,861<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,861<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Dec. 31, 2016</a></td>
<td class="nump">$ 122<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,311,229<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(30,358)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,241,380)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">39,613<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">39,613<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Dec. 31, 2016</a></td>
<td class="nump">121,636<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward', window );"><strong>Increase (Decrease) in Stockholders' Equity [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss)</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">346<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">346<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">346<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent', window );">Change in unrealized gains (losses), net of tax</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,334)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,334)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,334)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax', window );">Foreign currency translation</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(67)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(67)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(67)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodValueNewIssues', window );">Stock purchase</a></td>
<td class="text">&#160;<span></span>
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<td class="nump">$ 2<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 71,737<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 71,739<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 71,739<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesNewIssues', window );">Stock purchase (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,631<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross', window );">Issuance of common stock in connection with employee stock plans</a></td>
<td class="nump">$ 1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">22,931<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">22,932<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">22,932<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation', window );">Issuance of common stock in connection with employee stock plans (in shares)</a></td>
<td class="nump">1,709<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue', window );">Stock-based compensation expense</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">85,975<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">85,975<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">85,975<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary', window );">Issuance of Akcea Therapeutics, Inc. common stock in conjunction with intial public offering</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">157,270<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">157,270<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">157,270<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary', window );">Issuance of Akcea Therapeutics, Inc. common stock in conjunction with intial public offering (in shares)</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary', window );">Noncontrolling interest in Akcea Therapeutics, Inc. in conjunction with initial public offering</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(90,351)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(90,351)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">90,381<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">30<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest', window );">Noncontrolling interest in Akcea Therapetuics, Inc.</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(5,110)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(5,110)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(6,114)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(11,224)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Dec. 31, 2017</a></td>
<td class="nump">$ 125<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,553,681<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(31,759)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,241,034)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">281,013<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">84,267<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">365,280<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Dec. 31, 2017</a></td>
<td class="nump">124,976<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward', window );"><strong>Increase (Decrease) in Stockholders' Equity [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss)</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">273,741<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">273,741<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">273,741<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent', window );">Change in unrealized gains (losses), net of tax</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(280)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(280)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(280)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax', window );">Foreign currency translation</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">23<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">23<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">23<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodValueNewIssues', window );">Stock purchase</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 11<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 447,954<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 447,965<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 447,965<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesNewIssues', window );">Stock purchase (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">11,502<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross', window );">Issuance of common stock in connection with employee stock plans</a></td>
<td class="nump">$ 2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">27,898<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">27,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">27,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation', window );">Issuance of common stock in connection with employee stock plans (in shares)</a></td>
<td class="nump">1,451<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue', window );">Stock-based compensation expense</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">131,312<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">131,312<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">131,312<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest', window );">Noncontrolling interest in Akcea Therapetuics, Inc.</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(113,595)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(113,595)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">54,814<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(58,781)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance at Dec. 31, 2018</a></td>
<td class="nump">$ 138<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2,047,250<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (32,016)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (967,293)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,048,079<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 139,081<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,187,160<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rc">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharesIssued', window );">Balance (in shares) at Dec. 31, 2018</a></td>
<td class="nump">137,929<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></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_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Adjustment to additional paid in capital resulting from the redemption of convertible debt instruments as two separate components - a debt component and an equity component.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebtRedemption</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_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase in noncontrolling interest from subsidiary issuance of equity interests to noncontrolling interest holders in an initial public offering.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NoncontrollingInterestIncreaseFromNewIssuesBySubsidiary</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_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of new stock issued by subsidiary during the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_StockIssuedDuringPeriodSharesNewIssuesBySubsidiary</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_StockIssuedDuringPeriodValueNewIssuesBySubsidiary">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Equity impact of the value of new stock issued during the period by a subsidiary. Includes shares issued in an initial public offering or a secondary public offering.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_StockIssuedDuringPeriodValueNewIssuesBySubsidiary</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Adjustment to additional paid in capital resulting from the recognition of convertible debt instruments as two separate components - a debt component and an equity component. This bifurcation may result in a basis difference associated with the liability component that represents a temporary difference for purposes of applying accounting for income taxes. The initial recognition of deferred taxes for the tax effect of that temporary difference is as an adjustment to additional paid in capital.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 25<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=51819886&amp;loc=SL6014347-161799<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsToAdditionalPaidInCapitalEquityComponentOfConvertibleDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase to additional paid-in capital (APIC) from recognition of equity-based compensation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 20<br> -Section 55<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=109196918&amp;loc=d3e11149-113907<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5047-113901<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 20<br> -Section 55<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=109196918&amp;loc=d3e11178-113907<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 35<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=79507207&amp;loc=d3e4534-113899<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsToAdditionalPaidInCapitalTaxEffectFromShareBasedCompensation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase in additional paid in capital (APIC) resulting from a tax benefit associated with share-based compensation plan other than an employee stock ownership plan (ESOP). Includes, but is not limited to, excess tax benefit.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=27012166&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 718<br> -SubTopic 740<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109245112&amp;loc=d3e23524-113945<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsToAdditionalPaidInCapitalTaxEffectFromShareBasedCompensation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income (loss) and other comprehensive income (loss), attributable to noncontrolling interests. Excludes changes in equity resulting from investments by owners and distributions to owners.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4K<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591552-111686<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 21<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4613674-111683<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4569643-111683<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ComprehensiveIncomeNetOfTaxAttributableToNoncontrollingInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_CumulativeEffectOfNewAccountingPrincipleInPeriodOfAdoption">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax of increase (decrease) to equity or (increase) decrease to net assets, resulting from the cumulative effect adjustment of a new accounting principle applied in the period of adoption.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CumulativeEffectOfNewAccountingPrincipleInPeriodOfAdoption</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_IncreaseDecreaseInStockholdersEquityRollForward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInStockholdersEquityRollForward</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of profit or loss for the period, net of income taxes, which is attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<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 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&amp;loc=SL114874048-224260<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<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 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(18))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&amp;loc=SL114874131-224263<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 S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(20))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br><br>Reference 7: 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> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>
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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_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax and reclassification adjustments, of appreciation (loss) in value of unsold available-for-sale securities, attributable to parent entity. Excludes amounts related to other than temporary impairment (OTTI) loss.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (c)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 19<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4569616-111683<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4569643-111683<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeAvailableforsaleSecuritiesAdjustmentNetOfTaxPortionAttributableToParent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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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>
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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_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax, before reclassification adjustments of gain (loss) on foreign currency translation adjustments, foreign currency transactions designated and effective as economic hedges of a net investment in a foreign entity and intra-entity foreign currency transactions that are of a long-term-investment nature.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6450520&amp;loc=d3e32583-110901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=109240241&amp;loc=d3e32157-110900<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=109240241&amp;loc=d3e32211-110900<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 830<br> -SubTopic 30<br> -Section 45<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=109240241&amp;loc=d3e32022-110900<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 10A<br> -Subparagraph (a-c)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669646-108580<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 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=d3e637-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationGainLossArisingDuringPeriodNetOfTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharesIssued">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares of stock issued as of the balance sheet date, including shares that had been issued and were previously outstanding but which are now held in the treasury.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharesIssued</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodSharesNewIssues">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of new stock issued during the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=27012166&amp;loc=d3e187085-122770<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodSharesNewIssues</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares (or other type of equity) issued during the period as a result of any equity-based compensation plan other than an employee stock ownership plan (ESOP), net of any shares forfeited. Shares issued could result from the issuance of restricted stock, the exercise of stock options, stock issued under employee stock purchase plans, and/or other employee benefit plans.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=27012166&amp;loc=d3e187085-122770<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodValueNewIssues">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Equity impact of the value of new stock issued during the period. Includes shares issued in an initial public offering or a secondary public offering.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=27012166&amp;loc=d3e187085-122770<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&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(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodValueNewIssues</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_StockIssuedDuringPeriodValueShareBasedCompensationGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Gross value of stock (or other type of equity) issued during the period as a result of any equity-based compensation plan other than an employee stock ownership plan (ESOP). Stock issued could result from the issuance of restricted stock, the exercise of stock options, stock issued under employee stock purchase plans, and/or other employee benefit plans.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodValueShareBasedCompensationGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of stockholders' equity (deficit), net of receivables from officers, directors, owners, and affiliates of the entity, attributable to both the parent and noncontrolling interests. Amount excludes temporary equity. Alternate caption for the concept is permanent equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4568740-111683<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4I<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4590271-111686<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 15<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4568447-111683<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<DOCUMENT>
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<head>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6802436480">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF STOCKHOLDERS' EQUITY (Parenthetical)<br></strong></div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Mar. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember', window );">2 3/4 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInStockholdersEquityRollForward', window );"><strong>Increase (Decrease) in Stockholders' Equity [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>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_IncreaseDecreaseInStockholdersEquityRollForward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInStockholdersEquityRollForward</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember</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>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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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>
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<DOCUMENT>
<TYPE>XML
<SEQUENCE>40
<FILENAME>R8.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6817363104">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF CASH FLOWS - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract', window );"><strong>Operating activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="nump">$ 214,985<span></span>
</td>
<td class="num">$ (10,783)<span></span>
</td>
<td class="num">$ (60,400)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract', window );"><strong>Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Depreciation', window );">Depreciation</a></td>
<td class="nump">10,706<span></span>
</td>
<td class="nump">6,708<span></span>
</td>
<td class="nump">7,481<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AmortizationOfIntangibleAssets', window );">Amortization of patents</a></td>
<td class="nump">1,822<span></span>
</td>
<td class="nump">1,641<span></span>
</td>
<td class="nump">1,552<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments', window );">Amortization of premium (discount) on investments, net</a></td>
<td class="num">(1,013)<span></span>
</td>
<td class="nump">6,752<span></span>
</td>
<td class="nump">6,813<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AmortizationOfFinancingCosts', window );">Amortization of debt issuance costs</a></td>
<td class="nump">1,810<span></span>
</td>
<td class="nump">1,616<span></span>
</td>
<td class="nump">1,225<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AmortizationOfDebtDiscountPremium', window );">Amortization of convertible senior notes discount</a></td>
<td class="nump">33,363<span></span>
</td>
<td class="nump">30,920<span></span>
</td>
<td class="nump">23,890<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AmortizationOfLeasedAsset', window );">Amortization of long-term financing liability for leased facility</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">3,659<span></span>
</td>
<td class="nump">6,693<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensation', window );">Stock-based compensation expense</a></td>
<td class="nump">131,312<span></span>
</td>
<td class="nump">85,975<span></span>
</td>
<td class="nump">72,108<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainOnSaleOfInvestments', window );">Gain on investment in Regulus Therapeutics, Inc.</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(374)<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="top.Show.showAR( this, 'defref_ions_GainLossOnExtinguishmentOfFinancingLiability', window );">Loss on extinguishment of financing liability for leased facility</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">7,689<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">3,983<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredIncomeTaxesAndTaxCredits', window );">Deferred income taxes (including benefit from valuation allowance release)</a></td>
<td class="num">(290,516)<span></span>
</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="top.Show.showAR( this, 'defref_ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments', window );">Non-cash losses related to patents, licensing, property, plant and equipment and strategic investments</a></td>
<td class="nump">1,012<span></span>
</td>
<td class="nump">3,302<span></span>
</td>
<td class="nump">2,297<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInOperatingCapitalAbstract', window );"><strong>Changes in operating assets and liabilities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInContractWithCustomerAsset', window );">Contracts receivable</a></td>
<td class="nump">47,595<span></span>
</td>
<td class="nump">45,088<span></span>
</td>
<td class="num">(96,687)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInInventories', window );">Inventories</a></td>
<td class="nump">1,400<span></span>
</td>
<td class="num">(2,493)<span></span>
</td>
<td class="num">(590)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInOtherOperatingAssets', window );">Other current and long-term assets</a></td>
<td class="num">(29,348)<span></span>
</td>
<td class="num">(58,367)<span></span>
</td>
<td class="nump">1,603<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInIncomeTaxesReceivable', window );">Long-term income tax receivable</a></td>
<td class="num">(223)<span></span>
</td>
<td class="num">(9,114)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInAccountsPayable', window );">Accounts payable</a></td>
<td class="num">(655)<span></span>
</td>
<td class="nump">1,784<span></span>
</td>
<td class="num">(10,677)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable', window );">Income taxes</a></td>
<td class="num">(710)<span></span>
</td>
<td class="nump">435<span></span>
</td>
<td class="nump">1,069<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInOtherEmployeeRelatedLiabilities', window );">Accrued compensation</a></td>
<td class="nump">4,117<span></span>
</td>
<td class="nump">965<span></span>
</td>
<td class="nump">8,121<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities', window );">Accrued liabilities and deferred rent</a></td>
<td class="num">(17,023)<span></span>
</td>
<td class="nump">28,564<span></span>
</td>
<td class="nump">4,720<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInContractWithCustomerLiability', window );">Deferred contract revenue</a></td>
<td class="nump">494,254<span></span>
</td>
<td class="nump">30,182<span></span>
</td>
<td class="num">(85,306)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInOperatingActivities', window );">Net cash provided by (used in) operating activities</a></td>
<td class="nump">602,888<span></span>
</td>
<td class="nump">174,149<span></span>
</td>
<td class="num">(112,105)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract', window );"><strong>Investing activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquireAvailableForSaleSecuritiesDebt', window );">Purchases of short-term investments</a></td>
<td class="num">(1,794,735)<span></span>
</td>
<td class="num">(877,810)<span></span>
</td>
<td class="num">(300,912)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities', window );">Proceeds from the sale of short-term investments</a></td>
<td class="nump">882,824<span></span>
</td>
<td class="nump">557,369<span></span>
</td>
<td class="nump">364,572<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment', window );">Purchases of property, plant and equipment</a></td>
<td class="num">(13,608)<span></span>
</td>
<td class="num">(34,764)<span></span>
</td>
<td class="num">(7,107)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentsToAcquireLicensesAndOtherAssets', window );">Acquisition of licenses and other assets, net</a></td>
<td class="num">(4,044)<span></span>
</td>
<td class="num">(3,093)<span></span>
</td>
<td class="num">(4,421)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentsToAcquireCostMethodInvestments', window );">Purchase of strategic investments</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(2,500)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromSaleOfEquityMethodInvestments', window );">Proceeds from the sale of Regulus Therapeutics, Inc.</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">2,507<span></span>
</td>
<td class="nump">4,467<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInInvestingActivities', window );">Net cash (used in) provided by investing activities</a></td>
<td class="num">(929,563)<span></span>
</td>
<td class="num">(358,291)<span></span>
</td>
<td class="nump">56,599<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract', window );"><strong>Financing activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions', window );">Proceeds from equity, net</a></td>
<td class="nump">27,900<span></span>
</td>
<td class="nump">22,931<span></span>
</td>
<td class="nump">13,417<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceInitialPublicOffering', window );">Proceeds from issuance of common stock in Akcea Therapeutics, Inc. from its initial public offering, net of underwriters' discount</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">110,438<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromDebtNetOfIssuanceCosts', window );">Proceeds from building mortgage debt, net of issuance costs</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">59,750<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromLinesOfCredit', window );">Proceeds from borrowing on line of credit facility</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">4,000<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfPrivatePlacement', window );">Proceeds from the sale of Akcea Therapeutics, Inc. common stock to Novartis in a private placement</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">50,000<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsOfStockIssuanceCosts', window );">Offering costs paid</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(2,037)<span></span>
</td>
<td class="num">(818)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentToSettleFinancingLiabilityForLeasedFacility', window );">Payment to settle financing liability for leased facility</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(80,133)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ExcessTaxBenefitFromShareBasedCompensationFinancingActivities', window );">Excess tax benefits from stock-based compensation awards</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">1,861<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RepaymentsOfLongTermDebtAndCapitalSecurities', window );">Principal payments on debt and capital lease obligations</a></td>
<td class="nump">0<span></span>
</td>
<td class="num">(3,599)<span></span>
</td>
<td class="num">(7,066)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInFinancingActivities', window );">Net cash provided by financing activities</a></td>
<td class="nump">475,865<span></span>
</td>
<td class="nump">229,087<span></span>
</td>
<td class="nump">11,394<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsPeriodIncreaseDecrease', window );">Net increase (decrease) in cash and cash equivalents</a></td>
<td class="nump">149,190<span></span>
</td>
<td class="nump">44,945<span></span>
</td>
<td class="num">(44,112)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents at beginning of year</a></td>
<td class="nump">129,630<span></span>
</td>
<td class="nump">84,685<span></span>
</td>
<td class="nump">128,797<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents at end of year</a></td>
<td class="nump">278,820<span></span>
</td>
<td class="nump">129,630<span></span>
</td>
<td class="nump">84,685<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SupplementalCashFlowInformationAbstract', window );"><strong>Supplemental disclosures of cash flow information:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InterestPaidNet', window );">Interest paid</a></td>
<td class="nump">9,592<span></span>
</td>
<td class="nump">8,035<span></span>
</td>
<td class="nump">7,313<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashFlowNoncashInvestingAndFinancingActivitiesDisclosureAbstract', window );"><strong>Supplemental disclosures of non-cash investing and financing activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NonCashCapitalAndPatentExpenditures', window );">Amounts accrued for capital and patent expenditures</a></td>
<td class="nump">4,428<span></span>
</td>
<td class="nump">1,983<span></span>
</td>
<td class="nump">3,439<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CapitalExpendituresIncurredButNotYetPaid', window );">Purchases of property, plant and equipment included in long-term obligations</a></td>
<td class="nump">3,350<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NotesIssued1', window );">1 percent convertible senior notes principal issued related to our December 2016 debt exchange</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">185,450<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NotesReduction', window );">2 3/4 percent convertible senior notes principal extinguished related to our December 2016 debt exchange</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">61,099<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UnpaidDeferredOfferingCosts', window );">Unpaid deferred offering costs</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">291<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_MajorCustomersAxis=ions_BiogenIncMember', window );">Biogen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract', window );"><strong>Financing activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfCommonStock', window );">Proceeds from the issuance of common stock</a></td>
<td class="nump">447,965<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_MajorCustomersAxis=ions_NovartisInternationalAGMember', window );">Novartis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract', window );"><strong>Financing activities:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfCommonStock', window );">Proceeds from the issuance of common stock</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 71,737<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of write-down of assets recognized in the income statement. Includes, but is not limited to, losses from tangible assets, intangible assets and goodwill and an other than temporary decline in value that has been recognized against investments accounted for under the cost method of accounting.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AssetImpairmentChargesIncludingOtherThanTemporaryImpairmentInCostMethodInvestments</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_GainLossOnExtinguishmentOfFinancingLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Difference between the purchase price of the facility and the carrying value of our financing liability at the time of the purchase.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_GainLossOnExtinguishmentOfFinancingLiability</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_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the reporting period in the aggregate amount of expenses incurred but not yet paid and the change during the period in carrying value for all deferred liabilities due within one year or operating cycle.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_IncreaseDecreaseInAccruedLiabilitiesAndDeferredLiabilities</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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Future cash outflow to pay for purchases of fixed assets and patents that have been incurred.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NonCashCapitalAndPatentExpenditures</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PaymentToSettleFinancingLiabilityForLeasedFacility">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow paid to settle financing liability for leased facility.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentToSettleFinancingLiabilityForLeasedFacility</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_PaymentsToAcquireCostMethodInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow associated with the purchase of investments accounted for under the cost method of accounting.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentsToAcquireCostMethodInvestments</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_PaymentsToAcquireLicensesAndOtherAssets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow for acquisition of licenses and other assets not otherwise defined in the taxonomy.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentsToAcquireLicensesAndOtherAssets</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_UnpaidDeferredOfferingCosts">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Future cash outflow to pay for deferred offering costs attributable to an offering of securities that have been incurred.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UnpaidDeferredOfferingCosts</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The sum of the periodic adjustments of the differences between securities' face values and purchase prices that are charged against earnings. This is called accretion if the security was purchased at a discount and amortization if it was purchased at premium. As a noncash item, this element is an adjustment to net income when calculating cash provided by or used in operations using the indirect method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AmortizationOfDebtDiscountPremium">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of noncash expense included in interest expense to amortize debt discount and premium associated with the related debt instruments. Excludes amortization of financing costs. Alternate captions include noncash interest expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 1A<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&amp;loc=d3e28541-108399<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<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 S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03.8)<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AmortizationOfDebtDiscountPremium</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AmortizationOfFinancingCosts">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense attributable to debt issuance costs.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(8))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&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 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&amp;loc=d3e28555-108399<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AmortizationOfFinancingCosts</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AmortizationOfIntangibleAssets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate expense charged against earnings to allocate the cost of intangible assets (nonphysical assets not used in production) in a systematic and rational manner to the periods expected to benefit from such assets. As a noncash expense, this element is added back to net income when calculating cash provided by or used in operations using the indirect method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=6388964&amp;loc=d3e16225-109274<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AmortizationOfIntangibleAssets</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AmortizationOfLeasedAsset">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The expense charged against earnings for the periodic recognition of capitalized leases. This element may apply to energy companies that lease mineral producing properties and to other enterprises that capitalize property, plant, or equipment obtained through capital leases.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84164758&amp;loc=d3e45031-112735<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AmortizationOfLeasedAsset</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_CapitalExpendituresIncurredButNotYetPaid">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Future cash outflow to pay for purchases of fixed assets that have occurred.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=98513485&amp;loc=d3e4332-108586<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=98513485&amp;loc=d3e4313-108586<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=98513485&amp;loc=d3e4304-108586<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CapitalExpendituresIncurredButNotYetPaid</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_CashAndCashEquivalentsAtCarryingValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of currency on hand as well as demand deposits with banks or financial institutions. Includes other kinds of accounts that have the general characteristics of demand deposits. Also includes short-term, highly liquid investments that are both readily convertible to known amounts of cash and so near their maturity that they present insignificant risk of changes in value because of changes in interest rates. Excludes cash and cash equivalents within disposal group and discontinued operation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3044-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=82887183&amp;loc=d3e6676-107765<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.1)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashAndCashEquivalentsAtCarryingValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CashAndCashEquivalentsPeriodIncreaseDecrease">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in cash and cash equivalents. Cash and cash equivalents are the 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. Includes effect from exchange rate changes.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashAndCashEquivalentsPeriodIncreaseDecrease</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CashFlowNoncashInvestingAndFinancingActivitiesDisclosureAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashFlowNoncashInvestingAndFinancingActivitiesDisclosureAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredIncomeTaxesAndTaxCredits">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred income tax expense (benefit) and income tax credits.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredIncomeTaxesAndTaxCredits</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_Depreciation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of expense recognized in the current period that reflects the allocation of the cost of tangible assets over the assets' useful lives. Includes production and non-production related depreciation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_Depreciation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ExcessTaxBenefitFromShareBasedCompensationFinancingActivities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow from realized tax benefit related to deductible compensation cost reported on the entity's tax return for equity instruments in excess of the compensation cost for those instruments recognized for financial reporting purposes.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 20<br> -Section 55<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=109196918&amp;loc=d3e11374-113907<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ExcessTaxBenefitFromShareBasedCompensationFinancingActivities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_GainOnSaleOfInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The difference between the carrying value and the sale price of an investment.  A gain would be recognized when the sale price of the investment is greater than the carrying value of the investment.  This element refers to the Gain included in earnings and not to the cash proceeds of the sale.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(3)(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&amp;loc=SL114874131-224263<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br><br>Reference 3: http://www.xbrl.org/2009/role/commonPracticeRef<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(13))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&amp;loc=SL114874048-224260<br><br>Reference 4: http://www.xbrl.org/2009/role/commonPracticeRef<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(b)(9)(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br><br>Reference 5: http://www.xbrl.org/2009/role/commonPracticeRef<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(b)(7)(c))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainOnSaleOfInvestments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_GainsLossesOnExtinguishmentOfDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Difference between the fair value of payments made and the carrying amount of debt which is extinguished prior to maturity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=114001942&amp;loc=d3e12355-112629<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=114001942&amp;loc=d3e12317-112629<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainsLossesOnExtinguishmentOfDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInAccountsPayable">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the reporting period in the aggregate amount of liabilities incurred (and for which invoices have typically been received) and payable to vendors for goods and services received that are used in an entity's business.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInAccountsPayable</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInContractWithCustomerAsset">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in right to consideration in exchange for good or service transferred to customer when right is conditioned on something other than passage of time.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInContractWithCustomerAsset</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the reporting period in the amounts payable to taxing authorities for taxes that are based on the reporting entity's earnings, net of amounts receivable from taxing authorities for refunds of overpayments or recoveries of income taxes.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInIncomeTaxesPayableNetOfIncomeTaxesReceivable</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInIncomeTaxesReceivable">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the reporting period in income taxes receivable, which represents the amount due from tax authorities for refunds of overpayments or recoveries of income taxes paid.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInIncomeTaxesReceivable</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_IncreaseDecreaseInInventories">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The increase (decrease) during the reporting period in the aggregate value of all inventory held by the reporting entity, associated with underlying transactions that are classified as operating activities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInInventories</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInOperatingCapitalAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInOperatingCapitalAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInOtherEmployeeRelatedLiabilities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in employer-related costs classified as other and current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInOtherEmployeeRelatedLiabilities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInOtherOperatingAssets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in operating assets classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncreaseDecreaseInOtherOperatingAssets</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InterestPaidNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash paid for interest, excluding capitalized interest, classified as operating activity. Includes, but is not limited to, payment to settle zero-coupon bond for accreted interest of debt discount and debt instrument with insignificant coupon interest rate in relation to effective interest rate of borrowing attributable to accreted interest of debt discount.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=98513485&amp;loc=d3e4297-108586<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 17<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3367-108585<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 25<br> -Subparagraph (e)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3536-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InterestPaidNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInFinancingActivities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow (outflow) from financing activities, including discontinued operations. Financing activity cash flows include obtaining resources from owners and providing them with a return on, and a return of, their investment; borrowing money and repaying amounts borrowed, or settling the obligation; and obtaining and paying for other resources obtained from creditors on long-term credit.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3521-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInFinancingActivities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInInvestingActivities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow (outflow) from investing activities, including discontinued operations. Investing activity cash flows include making and collecting loans and acquiring and disposing of debt or equity instruments and property, plant, and equipment and other productive assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3521-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInInvestingActivities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInOperatingActivities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow (outflow) from operating activities, including discontinued operations. Operating activity cash flows include transactions, adjustments, and changes in value not defined as investing or financing activities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 25<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3536-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 24<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3521-108585<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInOperatingActivities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NotesIssued1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The fair value of notes issued in noncash investing and financing activities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=98513485&amp;loc=d3e4313-108586<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=98513485&amp;loc=d3e4332-108586<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=98513485&amp;loc=d3e4304-108586<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NotesIssued1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<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_NotesReduction">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The value of notes retired (or transferred to another entity) in noncash investing or financing transactions.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=98513485&amp;loc=d3e4332-108586<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=98513485&amp;loc=d3e4304-108586<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=98513485&amp;loc=d3e4313-108586<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NotesReduction</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsOfStockIssuanceCosts">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow for cost incurred directly with the issuance of an equity security.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsOfStockIssuanceCosts</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsToAcquireAvailableForSaleSecuritiesDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash outflow to acquire investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 13<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3213-108585<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3151-108585<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109979856&amp;loc=d3e26853-111562<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToAcquireAvailableForSaleSecuritiesDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow associated with the acquisition of long-lived, physical assets that are used in the normal conduct of business to produce goods and services and not intended for resale; includes cash outflows to pay for construction of self-constructed assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 13<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3213-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToAcquirePropertyPlantAndEquipment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromDebtNetOfIssuanceCosts">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from additional borrowings, net of cash paid to third parties in connection with debt origination.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromDebtNetOfIssuanceCosts</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_ProceedsFromIssuanceInitialPublicOffering">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow associated with the amount received from entity's first offering of stock to the public.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceInitialPublicOffering</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_ProceedsFromIssuanceOfCommonStock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from the additional capital contribution to the entity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfCommonStock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromIssuanceOfPrivatePlacement">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow associated with the amount received from entity's raising of capital via private rather than public placement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfPrivatePlacement</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow from issuance of shares under share-based compensation arrangement. Issuance includes, but is not limited to, exercise of stock options and similar instruments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=SL79508275-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromLinesOfCredit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow from contractual arrangement with the lender, including but not limited to, letter of credit, standby letter of credit and revolving credit arrangements.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<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.(f))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromLinesOfCredit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow from sale, maturity, prepayment and call of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3151-108585<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 12<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3179-108585<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109979856&amp;loc=d3e26853-111562<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow associated with the sale of equity method investments, which are investments in joint ventures and entities in which the entity has an equity ownership interest normally of 20 to 50 percent and exercises significant influence.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 12<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3179-108585<br></p></div>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromSaleOfEquityMethodInvestments</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (c)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4J<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591551-111686<br><br>Reference 7: 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 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3000-108585<br><br>Reference 8: 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 19<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4569616-111683<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8933-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4K<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591552-111686<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProfitLoss</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow associated with security instruments that either represent a creditor or an ownership relationship with the holder of the investment security with a maturity of beyond one year or normal operating cycle, if longer.  Includes repayments of (a) debt, (b) capital lease obligations, (c) mandatory redeemable capital securities, and (d) any combination of (a), (b), or (c).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -Subparagraph (a),(b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RepaymentsOfLongTermDebtAndCapitalSecurities</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate amount of noncash, equity-based employee remuneration. This may include the value of stock or unit options, amortization of restricted stock or units, and adjustment for officers' compensation. As noncash, this element is an add back when calculating net cash generated by operating activities using the indirect method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensation</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6972515760">
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<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>CONSOLIDATED STATEMENTS OF CASH FLOWS (Parenthetical)<br></strong></div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Mar. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2018</div></th></tr>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OrganizationConsolidationBasisOfPresentationBusinessDescriptionAndAccountingPoliciesTextBlock', window );">Organization and Significant Accounting Policies</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">1. Organization and Significant Accounting Policies</div><div><br /></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basis of Presentation</div><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals,&#160;Inc. (&#8220;we&#8221;, &#8220;us&#8221; or &#8220;our&#8221;) and the consolidated results of our majority-owned affiliate,&#160;Akcea Therapeutics, Inc., which we formed in December 2014. In July 2017, Akcea completed an initial public offering, or IPO, and therefore beginning in July 2017, we no longer own 100 percent of Akcea. </font>From the closing of Akcea&#8217;s IPO in July 2017 through mid-April 2018, we owned approximately 68 percent<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>of Akcea. In the second, third and fourth quarters of 2018, we received additional shares of Akcea&#8217;s stock related to our license of TEGSEDI and AKCEA-TTR-L<sub>Rx</sub> to Akcea, increasing our ownership percentage to approximately 75 percent. We reflected the increase in our ownership in these financial statements. In the first quarter of 2019, Akcea will pay us a $75 million sublicense fee in Akcea common stock, as a result of Novartis&#8217; license of AKCEA-APO(a)-L<sub>Rx</sub> in February 2019. We will receive 2.8 million shares of Akcea common stock for the sublicense fee. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Refer to the noncontrolling interest in Akcea section in this note for further information related to our accounting for our investment in Akcea.</font></font></div><div><br /></div><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Organization and Business Activity</div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation in April&#160;1991. We were organized principally to develop human therapeutic medicines using antisense technology. In December 2015, we changed our name from Isis Pharmaceuticals, Inc. to Ionis Pharmaceuticals, Inc.</font></div><div><br /></div><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic and Diluted Net Income (Loss) per Share</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Basic net income (loss) per share</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The calculation of total net income (loss) attributable to our common stockholders for 2018 and 2017 considered our net income for Ionis on a stand-alone basis plus our share of Akcea&#8217;s net loss for the period. During 2016, we owned 100 percent of Akcea. To calculate the portion of Akcea&#8217;s net loss attributable to our ownership for 2018 and 2017, we multiplied Akcea&#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our&#160;total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for 2018 and 2017.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our basic net income per share for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2018</font>, was calculated as follows (in thousands, except per share amounts):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2018</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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The change in our revenue was primarily due to:</div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>A change in how we recognize milestone payments:</u></font> Topic 606 requires us to amortize more of the milestone payments we achieve, rather than recognizing the milestone payments in full in the period in which we achieved the milestone event as we did under Topic 605. This change resulted in an increase in R&amp;D revenue recognized for 2017 and 2016 of $23.7 million and $24.1 million, respectively.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>A change in how we calculate revenue for payments we are recognizing into revenue over time:</u></font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> Under Topic 605, we amortized payments into revenue evenly over the period of our obligations. When we made a change to our estimated completion period, we recognized that change on a prospective basis. Under Topic 606, we are required to use an input method to determine the amount we amortize each reporting period. Each period we review our &#8220;inputs&#8221; such as our level of effort expended, including the time we estimate it will take us to complete the activities or costs incurred, relative to the total expected inputs to satisfy the performance obligation. For certain collaborations, such as Bayer and Novartis, the input method resulted in a change to the revenue we had previously recognized using a straight-line amortization method.</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">This change resulted in a decrease in our R&amp;D revenue of $15.1 million for 2017. This change did not result in an impact to our 2016 R&amp;D revenue.</font></font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our updated revenue recognition policy reflecting Topic 606 is as follows:</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Our Revenue Sources</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue, we include the amounts in deferred revenue on our consolidated balance sheet.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as commercial revenue future sales milestone payments and royalties we earn under our partnerships.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Commercial Revenue: TEGSEDI Product Sales, net</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We began adding product sales from TEGSEDI to our commercial revenue in the fourth quarter of 2018. </font>In the U.S., TEGSEDI is distributed through an exclusive distribution agreement with a third-party logistics company, or 3PL, that takes title to TEGSEDI. The 3PL is our sole customer in the U.S. The 3PL then distributes TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distribute TEGSEDI to health care providers and patients. In Germany, TEGSEDI is distributed through a non-exclusive distribution model with a 3PL that takes title to TEGSEDI. The 3PL is our sole customer in Germany. The 3PL in Germany then distributes TEGSEDI to hospitals and pharmacies.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Research and development revenue under collaborative agreements</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;D, services, and manufacturing services.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our collaboration agreements are detailed in Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements.</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>Under each collaboration note we discuss our specific revenue recognition conclusions, including our significant performance obligations under each collaboration.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Steps to Recognize Revenue</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use a five step process to determine the amount of revenue we should recognize and when we should recognize it. The five step process is as follows:</font></div><div><br /></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">1.</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Identify the contract</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the following criteria:</font></div><div><br /></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We and our partner approved the contract and we are both committed to perform our obligations;</font></div></td></tr></table></div></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have identified our rights, our partner&#8217;s rights and the payment terms;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the contract; and</font></div></td></tr></table></div></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe collectability is probable.</font></div></td></tr></table></div></div><div style="margin-bottom: 10pt;"><br /></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">2.</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Identify the performance obligations</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We next identify the distinct goods and services we are required to provide under the contract. Accounting rules refer to these as our performance obligations. We typically have only one performance obligation at the inception of a contract, which is to perform R&amp;D services.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Often times we enter into a collaboration agreement in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights. These items are contingent upon future events that may not occur. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation.</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">3.</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Determine the transaction price</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because the payments are not probable. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and are usually based on scientific progress. For example, in the first quarter of 2019, we earned a $35 million milestone payment from Roche when it dosed the first patient in the Phase 3 study of IONIS-HTT<sub>Rx</sub>.&#160; At December 31, 2018, we determined it was not probable that we could earn this milestone payment.&#160;As such, we did not recognize any revenue associated with it in 2018.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160; &#160;</font></font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">4.</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Allocate the transaction price</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling price.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement. We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected income to present value. The significant inputs we use to determine the projected income of a license could include:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Estimated future product sales;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Estimated royalties on future product sales;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Contractual milestone payments;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expenses we expect to incur;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income taxes; and</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A discount rate.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We typically estimate the selling price of R&amp;D services by using our internal estimates of the cost to perform the specific services. The significant inputs we use to determine the selling price of our R&amp;D services include:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The number of internal hours we estimate we will spend performing these services;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of work we will perform;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of work that we will contract with third parties to perform; and</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of API we will use.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For purposes of determining the stand-alone selling price of the R&amp;D services we perform and the API we will deliver, accounting guidance requires us to include a markup for a reasonable profit margin.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">5.</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Recognize revenue</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;D services. We recognize revenue at a point in time when our partner receives full use of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For R&amp;D services that we recognize over time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">change over the course of the collaboration, they may affect the timing and amount of revenue that we recognize in the current and future periods.</font></font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following are examples of when we typically recognize revenue based on the types of payments we receive.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize royalty revenue in the period in which the counterparty sells the related product, which in certain cases may require us to estimate our royalty revenue. </font>We recognize royalties from SPINRAZA sales in the period Biogen records the sale of SPINRAZA. Our accounting for SPINRAZA royalties did not change as a result of adopting Topic 606.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Commercial Revenue: TEGSEDI Product Sales, net</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize TEGSEDI product sales in the period </font>when our customer obtains control of TEGSEDI, which occurs at a point in time upon transfer of title to the customer. We classify payments to customers or other parties in the distribution channel for services that are distinct and priced at fair value as selling, general and administrative expenses in our consolidated statements of operations. Otherwise payments to customers or other parties in the distribution channel that do not meet those criteria are classified as a reduction of revenue, as discussed further below. We exclude from revenues, taxes collected from customers relating to product sales and remitted to governmental authorities.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Reserves for TEGSEDI Product Sales</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We record TEGSEDI product sales at our net sales price, or transaction price. We include in our transaction price estimated reserves for discounts, returns, chargebacks, rebates, co-pay assistance and other allowances that we offer within contracts between us and our customers, wholesalers, health care providers and other indirect customers. We estimate our reserves using the amounts we have earned or what we can claim on the associated sales. We classify our reserves as reductions of accounts receivable when the amount is payable to our customer or a current liability when the amount is payable to a party other than our customer in our consolidated balance sheet. In certain cases, our estimates include a range of possible outcomes that are probability-weighted for relevant factors such as our historical experience, current contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflect our best estimates under the terms of our respective contracts. When calculating our reserves and related product sales, we only recognize amounts to the extent that we consider it probable that we would not have to reverse in a future period a significant amount of the cumulative sales we previously recognized. The actual amounts we receive may ultimately differ from our reserve estimates. If actual amounts in the future vary from our estimates, we will adjust these estimates, which would affect our net TEGSEDI product sales in the respective period.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following are the components of variable consideration related to TEGSEDI product sales:</font></div><div><br /></div><div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Chargebacks: </font>In the U.S., we estimate obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charges us for the difference between what it pays for the product and the selling price to the qualified healthcare providers. We record reserves for these chargebacks related to TEGSEDI product sales to our U.S. customer during the reporting period. We also estimate the amount of product remaining in the distribution channel inventory at the end of the reporting period that we expect our customer to sell to wholesalers in future periods.</font></div><div><br /></div><div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Government rebates</font>: We are subject to discount obligations under government programs, including Medicaid programs and Medicare in the U.S. We estimate Medicaid and Medicare rebates based on a range of possible outcomes that are probability-weighted for the estimated payer mix. We record these reserves as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales in the same period we recognize the related sale. For Medicare rebates, we also estimate the number of patients in the prescription drug coverage gap for whom we will owe an additional liability under the Medicare Part D program. On a quarterly basis, we update our estimates and record any adjustments in the period that we identify the adjustments. In Germany, pharmaceutical companies must grant a specified rebate percentage to the German government. We include this rebate in the same period we recognize the related TEGSEDI product sales, resulting in a reduction of product sales.</font></div><div><br /></div><div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Trade discounts and allowances: </font>We provide customary invoice discounts on TEGSEDI product sales to our U.S. customer for prompt payment. We record this discount as a reduction of TEGSEDI product sales in the period in which we recognize the related product revenue. In addition, we receive and pay for various distribution services from our U.S. customer and wholesalers in our U.S. distribution channel. For services we receive that are either not distinct from the sale of TEGSEDI or for which we cannot reasonably estimate the fair value, we classify such fees as a reduction of TEGSEDI product sales.</font></div><div><br /></div><div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Product Returns: </font>Our U.S. customer has return rights and the wholesalers have limited return rights primarily related to the expiration date of the TEGSEDI product. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We estimate the amount of TEGSEDI product sales that our customer may return. We record our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale. Based on our distribution model for TEGSEDI, contractual inventory limits with our customer and wholesalers and the price of TEGSEDI, we believe we will have minimal returns. Our customer in Germany only takes title to the product once it receives an order from a hospital or pharmacy and therefore does not maintain any inventory of TEGSEDI, as such we do not estimate returns in Germany.</font></div><div><br /></div><div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Other incentives: </font>In the U.S., we estimate reserves for other incentives including co-payment assistance we provide to patients with commercial insurance who have coverage and reside in states that allow co-payment assistance. We record a reserve for the amount we estimate we will pay for co-payment assistance. We base our reserve on the number of estimated claims and our estimate of the cost per claim related to TEGSEDI product sales that we have recognized as revenue. We record our other incentive reserve estimates as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Research and development revenue under collaboration agreements:</u></font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Upfront Payments</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">When we enter into a collaboration agreement with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&amp;D services. For example, under our new <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">collaboration agreement with Roche to</font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> develop IONIS-FB-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;for the treatment of complement-mediated diseases</font>, we received a $75 million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our single performance obligation, R&amp;D services. We are amortizing the $75 million upfront payment using an input method over the estimated period of time we are providing R&amp;D services. Refer to <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font>, for further discussion. Under Topic 605, we amortized upfront payments evenly over the period of our obligation.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Milestone Payments</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are required to include additional consideration in the transaction price when it is probable. We typically include milestone payments for R&amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because there is considerable uncertainty in the research and development processes that trigger these payments under our collaboration agreements. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales based milestone payments in the period we achieve the milestone under the sales-based royalty exception allowed under accounting rules.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For example, in the third quarter of 2017, we initiated a Phase 1/2a clinical study of IONIS-MAPT<sub>Rx </sub>in patients with mild Alzheimer&#8217;s disease. We earned a $10 million milestone payment from Biogen related to the initiation of this study. Under Topic 606, we added this payment to the transaction price and allocated it to our R&amp;D services performance obligation. We are recognizing revenue from this milestone payment over our estimated period of performance. Under Topic 605, this milestone payment was recognized in full in the third quarter of 2017, which was the period in which we achieved the milestone event.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Conversely, we recognize in full those milestone payments that we earn based on our partners&#8217; activities when our partner achieves the milestone event. For example, in the third quarter of 2018, we recognized a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of IONIS-AZ4-2.5-L<sub>Rx</sub>. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We concluded that the milestone payment was not related to our R&amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any performance obligations related to this milestone payment. </font>Our revenue recognition of milestone payments we earn based on our partners&#8217; activities did not change as a result of adopting Topic 606.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>License Fees</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We generally recognize as revenue the total amount we determine to be the stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery. </font>For example, in the fourth quarter of 2018, we earned a $35 million license fee when Biogen licensed IONIS-SOD1<sub>Rx</sub> from us. Our recognition of license fees did not change as a result of adopting Topic 606.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Amendments to Agreements</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the accounting for the amendment:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If the goods and/or services are at a stand-alone selling price.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and at their stand-alone selling price, we then assess whether the remaining goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated revenue as a cumulative adjustment.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for the prevention of thrombosis. As part of the agreement, Bayer paid us a $100 million upfront payment. At the onset of the agreement, we were responsible for completing a Phase 2 study of IONIS-FXI</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and to initiate development of IONIS-FXI-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also eligible to receive milestone payments and tiered royalties on gross margins of IONIS-FXI</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and IONIS-FXI-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of IONIS-FXI-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, to provide R&amp;D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. </font>Refer to <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font>, for further discussion <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">of our accounting treatment for our Bayer collaboration. </font>Our allocation of the consideration we received for the Bayer amendment did not change as a result of adopting Topic 606. However, the method in which we are recognizing revenue related to our R&amp;D services performance obligation did change. We are amortizing revenue related to our R&amp;D services performance obligation using the input method under Topic 606.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Multiple Agreements</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the agreements were negotiated together with a single objective;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the goods and/or services promised under the agreements are a single performance obligation.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance requires us to account for them as a combined arrangement.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: a new strategic neurology collaboration agreement and a stock purchase agreement, or SPA. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis. Refer to Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for further discussion of the accounting treatment for the 2018 strategic neurology collaboration with Biogen.</font></font></div><div><br /></div><div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Contracts Receivable</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our contracts receivable balance represents the amounts we have billed our partners for goods we have delivered or services we have performed that are due to us unconditionally. When we bill our partners with payment terms based on the passage of time, we consider the contract receivable to be unconditional. We typically receive payment within one quarter of billing our partner</font>. Our contracts receivable balance as of December 31, 2017 did not change when we adopted Topic 606.</font></div><div><br /></div><div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Unbilled SPINRAZA Royalties</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet. </font>Our unbilled SPINRAZA royalties as of December 31, 2017 did not change when we adopted Topic 606.</font></div><div><br /></div><div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Deferred Revenue</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are often entitled to bill our customers and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.</font> During the years ended December 31, 2018 and 2017, we recognized $105.3 million and $95.1 million of revenue from amounts that were in our beginning deferred revenue balances for those periods, respectively. Refer to our revenue recognition policy above detailing how we recognize revenue for further discussion.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the adjustments we were required to make to our deferred revenue amounts to adopt Topic 606 (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">At December 31, 2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 605</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; 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The increase was primarily related to the change in the accounting for certain milestone payments and the way in which we amortize payments. Under Topic 605, we previously recognized the majority of the milestone payments we earned in the period we achieved the milestone event, which did not impact our deferred revenue balance. Under Topic 606 we are now amortizing more milestone payments over the period of our performance obligation, which adds to our deferred revenue balance. Additionally, under Topic 605 we amortized payments evenly over the period of our obligation. Under Topic 606, we are required to use an input method to determine the amount we amortize each reporting period. The increase in deferred revenue relates to agreements with the following partners:</div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$24.2 million from Biogen;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$15.9 million from AstraZeneca;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$11.8 million from Novartis; and</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$ 2.3 million from other partners.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cost of Products Sold</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We obtained the first regulatory approval for TEGSEDI in July 2018, as a result we began recognizing cost of products sold expenses related to TEGSEDI. Our cost of products sold includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the manufacturing and distribution of TEGSEDI. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of products sold. 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We expense research and development costs as we incur them. When we make payments for research and development services prior to the services being rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2018, 2017 and 2016, research and development expenses were $411.9 million, $372.5 million and $340.4 million, respectively. A portion of the costs included in research and development expenses are costs associated with our partner agreements. 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font-size: 10pt; font-weight: bold;">Noncontrolling Interest in Akcea Therapeutics, Inc.</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Prior to Akcea&#8217;s IPO in July 2017, we owned 100 percent of Akcea. From the closing of Akcea&#8217;s IPO in July 2017 through mid-April 2018, we owned approximately 68 percent<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>of Akcea. In the second, third and fourth quarters of 2018, we received additional shares of Akcea&#8217;s stock related to our license of TEGSEDI and AKCEA-TTR-L<sub>Rx</sub> to Akcea, increasing our ownership percentage to approximately 75 percent. We reflected this increase in our ownership percentage in these financial statements as an adjustment to noncontrolling interest. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The shares third parties own represent an interest in Akcea&#8217;s equity that is not controlled by us. However, as we continue to maintain overall control of Akcea through our voting interest, we reflect the assets, liabilities and results of operations of Akcea in our consolidated financial statements. We reflect the noncontrolling interest attributable to other owners of Akcea&#8217;s common stock in a separate line on the statement of operations and a separate line within stockholders&#8217; equity in our consolidated balance sheet. In addition, we record a noncontrolling interest adjustment to account for the stock options Akcea grants, which if exercised, will dilute our ownership in Akcea. This adjustment is a reclassification within stockholders&#8217; equity from additional paid-in capital to noncontrolling interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized.</font></font></div><div><br /></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Concentration of Credit Risk</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents, short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&#8217;s, Standard&#160;&amp; Poor&#8217;s, or S&amp;P, or Fitch, respectively. We have established guidelines relative to diversification and maturities that maintain safety and liquidity. 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We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments. We use the specific identification method to determine the cost of securities sold.</font></div><div><br /></div><div style="background-color: #FFFFFF;"><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies that we received as part of a technology license or partner agreement. At December 31, 2018, we held equity investments in two publicly held companies, ProQR Therapeutics N.V., or ProQR, and Antisense Therapeutics Limited, or ATL. We also held equity investments in four privately-held companies, Atlantic Pharmaceuticals Limited, Dynacure SAS, Seventh Sense Biosystems and Suzhou Ribo Life Science Co, Ltd.</font></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2018, we adopted the amended accounting guidance related to the recognition, measurement, presentation, and disclosure of certain financial instruments. The amended guidance requires us to measure and record our equity investments at fair value. Additionally, the amended accounting guidance requires us to recognize the changes in fair value in our consolidated statement of operations, instead of through accumulated other comprehensive income. Prior to 2018, we accounted for our equity investments in privately held companies under the cost method of accounting. Under the amended guidance we account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer. Our adoption of this guidance did not have an impact on our results.</font></div><div><br /></div><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Inventory Valuation</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We reflect our inventory on our consolidated balance sheet at the lower of cost or market value under the first-in, first-out method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials they have alternative future uses. We include in inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and, as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We expense these costs as R&amp;D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency.</font></div><div style="text-align: justify;"><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We obtained the first regulatory approval for TEGSEDI in July 2018. 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If no similar debt instrument exists, we estimate fair value by using assumptions that market participants would use in pricing a debt instrument, including market interest rates, credit standing, yield curves and volatilities. We use accounting estimates and assumptions when we determine the fair value of the debt component. These estimates and assumptions we use are judgmental in nature and could have a significant impact on the determination of the debt component, and the associated non-cash interest expense.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We assigned a value to the debt component of our convertible notes equal to the estimated fair value of similar debt instruments without the conversion feature, which resulted in us recording our debt at a discount. We are amortizing our debt issuance costs and debt discount over the life of the convertible notes as additional non-cash interest expense utilizing the effective interest method. For additional information, see Note 3, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Long-Term Obligations and Commitments</font>.</font></div><div><br /></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Segment Information</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have two operating segments, our Ionis Core segment and Akcea Therapeutics, our majority-owned affiliate. Akcea is </font>a biopharmaceutical company focused on developing and commercializing medicines to treat patients with rare and serious diseases<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. We provide segment financial information and results for our Ionis Core segment and our Akcea Therapeutics segment based on the segregation of revenues and expenses that our chief decision maker reviews to assess operating performance and to make operating decisions. We allocate a portion of Ionis&#8217; development, R&amp;D support and general and administrative expenses to Akcea for work Ionis performs on behalf of Akcea.</font></font></div><div><br /></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value Measurements</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity securities in publicly-held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify the majority of our securities as Level 2. We obtain the fair value of our Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and comparing that fair value to the fair value based on observable market prices. During 2018 and 2017, there were no transfers between our Level 1 and Level 2 investments. When we recognize transfers between levels of the fair value hierarchy, we recognize the transfer on the date the event or change in circumstances that caused the transfer occurs.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following tables present the major security types we held at December 31, 2018 and 2017 that are regularly measured and carried at fair value. 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Because Akcea completed its IPO before April 2018, Novartis will not purchase additional shares of Ionis stock. 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In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development credit carryforwards. We record a valuation allowance when necessary to reduce deferred tax assets to the amount we expect to realize.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes. Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for income taxes in the period in which such determination is made.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be realized.&#160;</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For U.S. federal income tax purposes, we are required to file separate U.S. federal income tax returns for Ionis and Akcea. We began deconsolidating Akcea for U.S. federal income tax purposes upon Akcea&#8217;s initial public offering. As a result, we are required to assess our Ionis stand-alone and Akcea&#8217;s valuation allowances separately even though we consolidate Akcea&#8217;s financial results in our consolidated financial statements. We continue to file combined state tax returns in most jurisdictions. As a result, we continue to assess the state portion of our valuation allowance for those jurisdictions on a consolidated basis.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have historically recorded a valuation allowance against all our net deferred tax assets due to cumulative financial statement losses. However, in the fourth quarter of 2018, we reversed the valuation allowance previously recorded against our Ionis stand-alone U.S. federal net deferred tax assets, resulting in a one-time non-cash tax benefit of $332.1 million. Given our current stand-alone Ionis pre-tax income, and assuming we maintain this current level of Ionis stand-alone pre-tax income, we expect to generate income before taxes in the U.S. in future periods at a level that would result in us fully utilizing our U.S. federal net operating loss carryforwards and most of our Research and Development and Orphan Drug tax credit carryforwards over the next three years.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We continue to maintain a full valuation allowance of $234.2 million against all of Akcea&#8217;s net deferred tax assets and the net state deferred tax assets of Ionis at December 31, 2018 due to uncertainties related to our ability to realize the tax benefits associated with these assets.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries.</font></div><div><br /></div><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Impact of Recently Issued Accounting Standards</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2016, the FASB issued amended accounting guidance related to lease accounting, which will require us to record all leases with a term longer than one year on our balance sheet. When we record leases on our balance sheet under the new guidance, we will record a liability with a value equal to the present value of payments we will make over the life of the lease (lease liability) and an asset representing the underlying leased asset (right of use asset). The new accounting guidance requires us to determine if our leases are operating or financing leases. We will record expense for operating leases on a straight-line basis as an operating expense. If we determine a lease is a financing&#160;lease, we will record both interest and amortization expense and generally the expense will be higher in the earlier periods of the lease. We adopted this guidance on January 1, 2019 and adjusted our opening balance sheet on that date. We elected the available practical expedients. The most significant impact was the recognition of right of use assets and lease liabilities for our operating leases. We are in the process of finalizing the impact of the adoption. The adoption will not have an impact on our consolidated statement of operations or statement of cash flows.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 2016, the FASB issued guidance that changes the measurement of credit losses for most financial assets and certain other instruments. If we have credit losses, this updated guidance requires us to record allowances for these instruments under a new expected credit loss model. This model requires us to estimate the expected credit loss of an instrument over its lifetime, which represents the portion of the amortized cost basis we do not expect to collect. The new guidance requires us to remeasure our allowance in each reporting period we have credit losses. The new standard is effective for annual and interim periods beginning after December 15, 2019. Early adoption is permitted for periods beginning after December 15, 2018. When we adopt the new standard, we will make any adjustments to beginning balances through a cumulative-effect adjustment to accumulated deficit on that date. We plan to adopt this guidance on January 1, 2020. We are currently assessing the effects it will have on our consolidated financial statements and disclosures.</font></div><div style="text-align: justify;"><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2018, the FASB issued updated guidance for reclassification of tax effects from accumulated other comprehensive income (loss). The updated guidance gives entities an option to reclassify amounts included in accumulated other comprehensive income (loss) that under the Tax Act do not have a way to be relieved, and allows a one-time reclassification to retained earnings. The updated guidance is effective for all entities for fiscal years beginning after December 31, 2018, and interim periods within those fiscal years. We have decided not to record the reclassification adjustments provided by this guidance.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 2018, the FASB issued updated guidance to simplify the accounting for stock-based compensation expense for nonemployees. Specifically, we are now expensing grants to nonemployees in a similar manner as grants to employees. Previously, we had to re-value these grants at each reporting period to reflect the current fair value. Under the amended guidance, we value grants to nonemployees when we grant them and we will not adjust their value for future changes. We adopted this guidance in the second quarter of 2018. The updated guidance did not have a material impact to our financial results.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In November 2018, the FASB issued clarifying guidance of the interaction between the collaboration accounting guidance and the new revenue recognition guidance we adopted on January 1, 2018 (Topic 606). The clarifying guidance included the following:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">When a participant is considered a customer in a collaborative arrangement, all of the associated accounting under Topic 606 should be applied;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Adds &#8220;unit of account&#8221; concept to collaboration accounting guidance to align with Topic 606. This is used to determine if revenue is recognized or if a contra expense is recognized from consideration received under a collaboration; and</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Precludes revenue from being recognized under Topic 606 when a transaction with a collaborative partner is determined not be a customer and is not directly related to the sales to third parties.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The updated guidance is effective for public entities for fiscal years beginning after December 15, 2019, and interim periods within those fiscal years. Early adoption is permitted. We plan to adopt this guidance on January 1, 2020. We are currently assessing the effects it will have on our consolidated financial statements and disclosures.</font></div><div><br /></div></div><span></span>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Investments<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentsAbstract', window );"><strong>Investments [Abstract]</strong></a></td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_invest_InvestmentTextBlock', window );">Investments</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">2. Investments</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">As of December 31, 2018, we had primarily invested our excess cash in debt instruments of the U.S. Treasury, financial institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&#8217;s, Standard &amp; Poor&#8217;s, or S&amp;P, or Fitch, respectively. We have established guidelines relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2018:</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">One year or less</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">77</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">After one year but within two years</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">20</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">After two years but within three and one half years</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">100</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr></table><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">As illustrated above, at December 31, 2018, 97 percent of our available-for-sale securities had a maturity of less than two years.</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize all of these securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the balance sheet date.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At December 31, 2018, we had an ownership interest of less than 20 percent <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">in four private companies and two public companies with which we conduct business. The privately-held companies are </font>Atlantic Pharmaceuticals Limited, Dynacure SAS, Seventh Sense Biosystems and Suzhou Ribo Life Science Co, Ltd.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The publicly traded companies are ATL and ProQR. </font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following is a summary of our investments (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31, 2018</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; 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We believe it is more likely than not that we will be able to hold these securities to maturity. Therefore, we anticipate full recovery of our debt securities&#8217; amortized cost basis at maturity.</div><div><br /></div></div><span></span>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">3. 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width: 76%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Carrying value of equity component</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">219,011</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 2015, we entered into a five-year revolving line of credit agreement with Morgan Stanley Private Bank, National Association, or Morgan Stanley. We amended the credit agreement in February 2016 to increase the amount available for us to borrow. Under the amended credit agreement, we can borrow up to a maximum of $30 million of revolving credit for general working capital purposes. 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,067</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2020</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; 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text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">694,774</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2022</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,809</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,494</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Thereafter</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">68,108</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">800,582</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; 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margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Less: fixed and determinable interest</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(41,837</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Less: unamortized portion of debt discount</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(111,426</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Plus: Deferred rent</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,960</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; 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We lease this space under a non-cancelable operating lease with an initial term ending in June 2021 and an option to extend the lease for up to two five-year periods.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additionally, we lease office space that we sublease to Akcea. We lease this space under a non-cancelable operating lease with an initial term ending in June 2023 and an option to extend the lease for one five-year period. The sublease with Akcea is eliminated in our consolidated financial statements. 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Under the lease agreement, Akcea received a three-month free rent period, which commenced on August 15, 2018, and a tenant improvement allowance up to $3.8 million. Akcea provided the lessor with a letter of credit to secure its obligations under the lease in the initial amount of $2.4 million, to be reduced to $1.8 million on the third anniversary of the rent commencement date and to $1.2 million on the fifth anniversary of the rent commencement date if Akcea meets certain conditions set forth in the lease at each such time. 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vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,862</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total minimum payments</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; 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We recognized rent expense on a straight line basis over the lease term for the lease on our building adjacent to our manufacturing facility, the office building that Akcea subleases and Akcea&#8217;s office space, which resulted in a deferred rent balance of $5.0 million and $0.1 million at December 31, 2018 and 2017, respectively.</div><div><br /></div></div><span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for debt and capital lease obligations can be reported. 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. Also includes descriptions and amounts of capital leasing arrangements that consist of direct financing, sales type and leveraged leases. Disclosure may include the effect on the balance sheet and the income statement resulting from a change in lease classification for leases that at inception would have been classified differently had guidance been in effect at the inception of the original lease.</p></div>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2018</div></th></tr>
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<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">4. Stockholders</font>&#8217;<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Equity</font></div><div><br /></div><div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Preferred Stock</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are authorized to issue up to 15,000,000 shares of &#8220;blank check&#8221; Preferred Stock. As of December 31, 2018, there were no shares of Preferred Stock outstanding. We have designated Series&#160;C Junior Participating Preferred Stock but have no issued or outstanding shares as of December 31, 2018.</font></div><div><br /></div><div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Common Stock</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At December 31, 2018 and 2017, we had 300,000,000 shares of common stock authorized, of which 137,928,828 and 124,976,373 were issued and outstanding, respectively. As of December 31, 2018, total common shares reserved for future issuance were 14,839,373.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">During the years ended December 31, 2018, 2017 and 2016, we issued 1,451,000, 1,709,000 and 1,285,000 shares of common stock, respectively, for stock option exercises, vesting of restricted stock units, and ESPP purchases. We received net proceeds from these transactions of $27.9 million, $22.9 million and $13.7 million in 2018, 2017 and 2016, respectively.</font></div><div><br /></div><div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Stock Plans</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">1989 Stock Option Plan</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as amended, provides for the issuance of non-qualified and incentive stock options for the purchase of up to 20,000,000 shares of common stock to our employees, directors, and consultants. The plan expires in January 2024. The 1989 Plan does not allow us to grant stock bonuses or restricted stock awards and prohibits us from repricing any options outstanding under the plan unless our stockholders approve the repricing. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. At December 31, 2018, a total of 848,753 options were outstanding, of which options to purchase 831,656 shares were exercisable, and 42,925 shares were available for future grant under the 1989 Plan.</font></div><div><br /></div><div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">2011 Equity Incentive Plan</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In March 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to our employees, directors, and consultants.&#160;In June 2015 and in May 2017, after receiving approval from our stockholders, we amended our 2011 Equity Incentive Plan to increase the total number of shares reserved for issuance. We increased the shares available under our 2011 Equity Incentive Plan from 5,500,000 to 11,000,000 in June 2015 and from 11,000,000 to 16,000,000 in May 2017. The plan expires in June&#160;2021. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only options and restricted stock unit awards to our employees, directors and consultants. Under the 2011 Plan, stock options cannot vest in a period of less than two years and restricted stock unit awards cannot vest in a period of less than three years. We have granted restricted stock unit awards to our employees under the 2011 Plan which vest annually over a four-year period. At December 31, 2018, a total of 9,705,441 options were outstanding, of which 4,801,904 were exercisable, 1,183,154 restricted stock unit awards were outstanding, and 3,340,351 shares were available for future grant under the 2011 Plan.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a change in control. In the absence of such provisions, no such acceleration will occur. The stock options and restricted stock unit awards we issue to our chief executive officer and issued to B. Lynne Parshall in her former role as chief operating officer will accelerate upon a change of control, as defined in the 2011 Plan. In addition, we implemented a change of control and severance benefit plan that provides for change of control and severance benefits to our executive officers, including our chief executive officer and chief financial officer. If we terminate one of our executive officers or if an executive officer resigns for good reason during the period that begins three months before and ends twelve months following a change in control of the company, the impacted executive officers&#8217; stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the termination date.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Corporate Transactions and Change in Control under 2011 Plan</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more of the following actions with respect to outstanding stock awards under the 2011&#160;Plan:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; 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vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Federal</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Convertible debt</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-size: 10pt;">We have adjusted all prior year tax amounts to reflect the tax impact of our adoption of Topic 606.</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have historically recorded a valuation allowance against all our net deferred tax assets due to cumulative financial statement losses. However, in the fourth quarter of 2018, we reversed the valuation allowance previously recorded against Ionis&#8217; stand-alone U.S. federal net deferred tax assets, resulting in a one-time non-cash tax benefit of $332.1 million. Given our current stand-alone Ionis pre-tax income, and assuming we maintain this current level of Ionis stand-alone pre-tax income, we expect to generate income before taxes in the U.S. in future periods at a level that would result in us fully utilizing our U.S. federal net operating loss carryforwards and most of our Research and Development and Orphan Drug tax credit carryforwards over the next three years.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We continue to maintain a full valuation allowance of $234.2 million against all of Akcea&#8217;s net deferred tax assets and the net state deferred tax assets of Ionis at December 31, 2018 due to uncertainties related to our ability to realize the tax benefits associated with these assets.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our valuation allowance decreased by $234.5 million from December 31, 2017 to December 31, 2018.&#160; The net decrease relates primarily to the reversal of the valuation allowance previously recorded against Ionis&#8217; stand-alone U.S. federal net deferred tax assets, offset by current year utilization of a portion of our net operating loss carry forwards.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At December 31, 2018, we had federal and state, primarily California, tax net operating loss carryforwards of $284.6 million and $808.7 million, respectively. Our federal tax loss carryforwards will begin to expire in 2033, unless we use them before then. Our California loss carryforwards continued to expire in 2018. At December 31, 2018, we also had federal and California research and development tax credit carryforwards of $288.9 million and $68.4 million, respectively. Our Federal research and development tax credit carryforwards began to expire in 2018. Our California research and development tax credit carryforwards are available indefinitely.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the ownership change limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation may result in the expiration of net operating losses and credits before utilization.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">On December 22, 2017, the U.S. government enacted comprehensive tax legislation commonly referred to as the Tax Cuts and Jobs Act of 2017, or the Tax Act. The Tax Act made broad and complex changes to the U.S. tax code, including, but not limited to, reducing the U.S. federal corporate income tax rate to 21 percent, imposing a mandatory one-time transition tax on certain unrepatriated earnings of foreign subsidiaries and eliminating the corporate alternative minimum tax, or AMT, and changing how existing AMT credits can be realized. We were required to recognize the tax effect of the tax law changes the year of enactment. In order to calculate these effects, we were required to determine the transition tax amount, remeasure our U.S. deferred tax assets and liabilities, and consider the impact to our AMT tax credit carryforwards. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For the year ended December 31, 2017, we recorded provisional amounts in accordance with that guidance where it was possible for us to make reasonable estimates of the effects of the Tax Act. We evaluated the decrease in our corporate tax rate and recorded a provisional, one-time tax expense of $107.3 million at December 31, 2017. We fully offset our tax effect by a decrease in our valuation allowance which resulted in no net tax effect in 2017.</font> During the fourth quarter of 2018, we completed our accounting for all aspects of the Tax Act. 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,495</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11,847</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ending balance of unrecognized tax benefits</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; 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text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">78,014</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">66,999</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td></tr></table><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Included in the balance of unrecognized tax benefits at December&#160;31, 2018, is $55.5 million that could impact our effective tax rate, subject to our remaining valuation allowance.</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not foresee any material changes to our gross unrecognized tax benefits within the next twelve months.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize interest and/or penalties related to income tax matters in income tax expense. We did not recognize any accrued interest and penalties related to gross unrecognized tax benefits during the year ended December 31, 2018.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are subject to taxation in the U.S. and various state and foreign jurisdictions. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our tax years for 1999 through 2018 are subject to examination by the U.S. federal, state and foreign tax authorities.</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries as we consider those earnings to be permanently reinvested. 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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CollaborativeArrangementDisclosureTextBlock', window );">Collaborative Arrangements and Licensing Agreements</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">6. Collaborative Arrangements and Licensing Agreements</div><div><br /></div><div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Strategic Partnership</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Biogen</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen&#8217;s expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with spinal muscular atrophy, or SMA. In</font> December 2017, we entered into a collaboration with Biogen to identify <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">new antisense medicines for the treatment of SMA</font>. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Additionally, we and Biogen are currently developing six other medicines to treat neurodegenerative diseases under these collaborations, including IONIS-SOD1</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for ALS, IONIS-MAPT</font><sub>Rx </sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">for Alzheimer&#8217;s disease</font><sub>,</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> IONIS-C9</font><sub>Rx </sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">for ALS, and IONIS-BIIB6</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, IONIS-BIIB7</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and IONIS-BIIB8</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> to treat undisclosed neurodegenerative diseases. In addition to these medicines, we and Biogen are evaluating numerous additional targets to develop medicines to treat neurological diseases. In April 2018, we entered into a new strategic collaboration for the treatment of neurological diseases with Biogen. From inception through December 2018, we have received over $2.0 billion from our Biogen collaborations, including $1 billion we received from Biogen in the second quarter of 2018 for our 2018 strategic neurology collaboration.</font></font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Spinal Muscular Atrophy Collaborations</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">SPINRAZA</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2012, we entered into a collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA. Biogen reported in </font>January 2019 that SPINRAZA was approved in over 40 countries around the world. In February 2019, SPINRAZA was approved in China. Biogen is responsible for global SPINRAZA commercial activities.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From inception through December 2018, we earned more than $785 million in total revenue under our SPINRAZA collaboration, including more than $350 million in revenue from SPINRAZA royalties and more than $435 million in R&amp;D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on any net sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible for all further global development, regulatory and commercialization activities and costs for SPINRAZA.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Over the course of our SPINRAZA collaboration, we identified two performance obligations, which were to perform R&amp;D services and to deliver the SPINRAZA license to Biogen. As we achieved milestone payments for our R&amp;D services, we included these amounts in our transaction price for our R&amp;D services performance obligation. We recognized revenue for our R&amp;D services performance obligation over our period of performance through December 2016. We recognized the $75 million license fee for SPINRAZA as revenue when we delivered the license to Biogen in July 2016 because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also earned additional milestone payments subsequent to delivering the license to Biogen that we recognized in full in the period each milestone payment became probable because we did not have a performance obligation related to each milestone payment. For example, we received $90 million of milestone payments for the approval of SPINRAZA in the EU and Japan in 2017 and recognized the full amounts into revenue in the period Biogen achieved the milestone events.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">New antisense medicines for the treatment of SMA</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December 2017, we entered into a collaboration agreement with Biogen to </font>identify <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">new antisense medicines for the treatment of SMA</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Biogen will have the option to license therapies arising out of this collaboration following the completion of preclinical studies. Upon licensing, Biogen </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">will be responsible for all further global development, regulatory and commercialization activities and costs for such therapies</font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. Under the collaboration agreement, we received a&#160;</font>$25 million<font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;upfront payment in December 2017. We will receive development and regulatory milestone payments from Biogen if new medicines advance towards marketing approval. </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In total over the term of our collaboration, we are eligible to receive up to $1.2 billion in license fees, milestone payments and other payments, including up to $80 million for the achievement of development milestones, up to $180 million for the achievement of commercialization milestones and up to $800 million for the achievement of sales milestones. In addition, we are eligible to receive tiered royalties </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">from the mid-teens to </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">mid-20 percent range </font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">on net sales.</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> We will achieve the next payment of up to $60 million</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">for the license of a medicine under this collaboration. </font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services for Biogen. We determined the transaction price to be the $25 million upfront payment we received when we entered into the collaboration. We allocated the transaction price to our single performance obligation. We are recognizing revenue for our R&amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently estimate we will satisfy our performance obligation in</font> December 2020.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Neurology Collaborations</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">2018 Strategic Neurology</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In April 2018, we and Biogen entered into a new strategic collaboration to develop novel antisense medicines for a broad range of neurological diseases and entered into a SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for these diseases for 10 years. We are responsible for the identification of antisense drug candidates based on selected targets</font>.&#160;Biogen is responsible for conducting IND-enabling toxicology studies for the selected target. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Biogen will have the option to license the selected target </font>after it completes the IND-enabling toxicology study. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If Biogen exercises its option for a medicine, it will assume </font>all <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">further global development, regulatory and commercialization responsibilities and costs for that medicine.&#160;</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the second quarter of 2018, we received </font>$1 billion from Biogen, comprised of $625 million to purchase our stock at an approximately 25 percent cash premium and $375 million in an upfront payment. <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are eligible to receive up to $270 million in milestone payments for each medicine that achieves marketing approval. </font>In addition, we are eligible to receive tiered royalties <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">up to the 20 percent</font> range <font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;">on net sales.</font> From inception through December 2018, we have received over $1 billion in payments under this collaboration, including $15 million we received in the fourth quarter of 2018 for advancing two targets under this collaboration. We will achieve the next payment of $7.5 million if Biogen designates a target<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> under this collaboration. </font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, </font>we identified one performance obligation, which was to perform R&amp;D services for Biogen.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> We determined our transaction price to be $552 million, comprised of $375 million from the upfront payment and $177 million for the premium paid by Biogen for its purchase of our common stock.</font> We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of marketability discount. We included a lack of marketability discount in our valuation of the premium because Biogen received restricted shares. We allocated the transaction price to our single performance obligation. In the fourth quarter of 2018, we received $15 million in milestone payments when we advanced <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">two </font>targets under this collaboration. We added these payments to our transaction price for our R&amp;D services performance obligation. We are recognizing revenue for our R&amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently estimate we will satisfy our performance obligation in </font>June 2028.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">2013 Strategic Neurology</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In September&#160;2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen will have the option to license antisense medicines after Phase 2 proof of concept. In October 2016, we expanded our collaboration to include additional research activities we will perform. If Biogen exercises its option for a medicine, it will assume all further global development, regulatory and commercialization responsibilities and costs for that medicine. We are currently advancing five medicines, IONIS-SOD1<sub>Rx</sub>, IONIS-C9<sub>Rx</sub>, IONIS-BIIB6<sub>Rx</sub>, IONIS-BIIB7<sub>Rx</sub> and IONIS-BIIB8<sub>Rx</sub> under this collaboration. In the fourth quarter of 2018, Biogen licensed IONIS-SOD1<sub>Rx</sub>, and as a result Biogen now is responsible for all further global development, regulatory and commercialization activities and costs for IONIS-SOD1<sub>Rx</sub>.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone payments, license fees and royalty payments for all medicines developed through this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug discovery and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee and milestone payments per program. The $260 million per program consists of approximately $60 million in development milestones, including amounts related to the cost of clinical trials, and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any antisense medicines developed under this collaboration. From inception through December 2018, we have received over $210 million in upfront fees, milestone payments and other payments under this collaboration, not including a $5 million milestone payment we earned in the fourth quarter of 2018 for Biogen&#8217;s initiation of a Proof of Concept study for IONIS-SOD1<sub>Rx </sub>which we received in the first quarter of 2019. We will achieve the next payment of up to $10 million if we advance a program under this collaboration.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of our strategic neurology collaboration, we identified one performance obligation, which was to perform R&amp;D services for Biogen. At inception, we determined the transaction price to be the $100 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&amp;D services, we include these amounts in our transaction price for our R&amp;D services performance obligation. We are recognizing revenue for our R&amp;D services performance obligation based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. </font>We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently estimate we will satisfy our performance obligation in</font> September 2019. From inception through December <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2018</font>, we have included $145 million in total payments in the transaction price for our R&amp;D services performance obligation. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the third quarter of 2018, we earned a $10 million milestone payment when Biogen initiated a Phase 1 study of IONIS-C9</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. We concluded that the milestone payment was not related to our R&amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any performance obligations related to this milestone payment.</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We identified a second performance obligation upon Biogen&#8217;s license of IONIS-SOD1<sub>Rx</sub> in the fourth quarter of 2018 because the license we granted to Biogen is distinct from our other performance obligation. We recognized the $35 million license fee for IONIS-SOD1<sub>Rx</sub> as revenue at that time because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen. Additionally, in the fourth quarter of 2018 we <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">earned a $5 million milestone when Biogen initiated a Proof-of-Concept study for IONIS-SOD1</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. We concluded that the milestone payment was not related to our R&amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the fourth quarter of 2018 because we do not have any performance obligations related to this milestone payment.</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Neurology</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December&#160;2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense medicines to up to three targets to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the programs through the completion of the first Phase 2 study for each program. We are currently advancing IONIS-MAPT<sub>Rx</sub> for Alzheimer&#8217;s disease under this collaboration. If Biogen exercises its option for a medicine, it will assume all further global development, regulatory and commercialization responsibilities and costs for that medicine.&#160;</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of the agreement, we received an upfront payment of $30 million. Over the term of the collaboration, we are eligible to receive up to $210 million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. The $210 million per program consists of up to $10 million in development milestone payments, plus a mark-up on the cost estimate of the Phase 1 and 2 studies and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each of the three programs. From inception through December 2018, we have received $58 million in milestone payments and upfront fees under this collaboration. We will achieve the next payment of $7.5 </font>million if we continue to advance IONIS-MAPT<sub>Rx</sub>.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services for Biogen. At inception, we determined the transaction price to be the $30 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&amp;D services, we include these amounts in our transaction price for our R&amp;D services performance obligation. We are recognizing revenue for our R&amp;D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently estimate we will satisfy our performance obligation in </font>December 2020. From inception through December<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> 2018</font>, we have included $40 million in total payments in the transaction price for our R&amp;D services performance obligation.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: left; text-indent: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties (commercial revenue)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; 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font-style: italic;">AstraZeneca</div><div style="text-align: justify;"><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Cardiac, Renal and Metabolic Diseases Collaboration</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In July 2015, we and AstraZeneca formed a collaboration to discover and develop antisense therapies for treating cardiac, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed three medicines from us: IONIS-AZ4-2.5-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, a medicine we designed to treat cardiovascular disease and our first </font>medicine that combines our Generation 2.5 and<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> LICA technology, IONIS-AZ5-2.5</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, a medicine we designed to </font>treat a genetically associated form of kidney disease and <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS-AZ6-2.5-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, a medicine we designed to </font>inhibit an undisclosed target to treat patients with nonalcoholic steatohepatitis, or NASH<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. AstraZeneca is responsible for all further global development, regulatory and commercialization activities and costs for each of the medicines it has licensed and any other future medicines AstraZeneca licenses.</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of the agreement, we received a $65 million upfront payment. We are eligible to receive license fees and milestone payments of up to more than $4 billion as medicines under this collaboration advance, including up to $1.1 billion for the achievement of development milestones and up to $2.9 billion for regulatory milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. From inception through December 2018, we have received over $165 million in upfront fees, license fees, milestone payments, and other payments under this collaboration, including a $10 million milestone payment we earned in the third quarter of 2018 when AstraZeneca initiated a Phase 1 trial for IONIS-AZ4-2.5-L<sub>Rx</sub>. We will achieve the next payment of $10 million under this collaboration if we advance a medicine under this collaboration<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">.</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">At the commencement of this collaboration, we identified one performance obligation, which was to perform R&amp;D services for AstraZeneca. We determined the transaction price to be the $65 million upfront payment we received and we allocated it to our single performance obligation. We are recognizing revenue for our R&amp;D services performance obligation as we perform services based on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> currently estimate we will satisfy this performance obligation in</font> August 2021. As we achieve milestone payments for our R&amp;D services, we include these amounts in our transaction price for our R&amp;D services performance obligation. 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Additionally, we did not have any further performance obligations related to the licenses after we delivered them to AstraZeneca.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In the third quarter of 2018, we earned a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of IONIS-AZ4-2.5-L<sub>Rx</sub>. We concluded that the milestone payment was not related to our R&amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any performance obligations related to this milestone payment.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Oncology Collaboration</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In December&#160;2012, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense medicines to treat cancer.&#160;As part of the agreement, we granted AstraZeneca an exclusive license to develop and commercialize </font>danvatirsen (formerly <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">IONIS-STAT3-2.5</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">) for the treatment of cancer. AstraZeneca is now responsible for all global development, regulatory and commercialization activities for </font>danvatirsen<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. We and AstraZeneca have evaluated </font>danvatirsen<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in people with head and neck cancer, advanced lymphoma and advanced metastatic hepatocellular carcinoma. AstraZeneca is evaluating </font>danvatirsen<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in combination with durvalumab, AstraZeneca&#8217;s PD-L1 blocking drug, in people with head and neck cancer, metastatic bladder cancer and metastatic non-small cell lung cancer. We and AstraZeneca also established an oncology research program. AstraZeneca has the option to license medicines resulting from the program, and if AstraZeneca exercises its option for a medicine, it will be responsible for all further global development, regulatory and commercialization activities and costs for such medicine. In the fourth quarter of 2018, we added </font>IONIS-AZ7-2.5<sub>Rx</sub> to our preclinical pipeline, a second drug under our oncology collaboration.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Under the terms of this agreement, we received $31 million in upfront payments. We are eligible to receive milestone payments and license fees from AstraZeneca as programs advance in development. 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Janssen has the option to license medicines from us through the designation of a development candidate for up to three programs. Under our collaboration, Janssen licensed IONIS-JBI1-2.5<sub>Rx</sub> in July 2016 and IONIS-JBI2-2.5<sub>Rx</sub> in November 2017. Janssen is currently conducting a Phase 1 study of IONIS-JBI1-2.5<sub>Rx</sub> and IONIS-JBI2-2.5<sub>Rx</sub> is in preclinical development. Prior to option exercise we are responsible for the discovery activities to identify development candidates. If Janssen exercises an option for any of the programs, it will be responsible for the global development, regulatory and commercial activities under that program. Under the terms of the agreement, we received $35 million in upfront payments. 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Akcea is responsible for completing a Phase 2 program, conducting an end-of-Phase 2 meeting with the FDA and providing initial quantities of API for each medicine. If Novartis exercises an option for either of these medicines, Novartis will be responsible for all further global development, regulatory and co-commercialization activities and costs for such medicine.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Akcea received a $75 million upfront payment in the first quarter of 2017, of which it retained $60 million and paid us $15 million as a sublicense fee. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2019, Novartis licensed AKCEA-APO(a)-L</font><sub>Rx</sub> and we earned a $150 million license fee. Akcea will pay us $75 million as a sublicense fee in 2.8 million shares of Akcea common stock. Novartis is responsible for conducting and funding all future development, regulatory and commercialization activities for AKCEA-APO(a)-L<sub>Rx</sub>, including a global pivotal cardiovascular outcomes study, for which planning and initiation activities are underway.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>If Novartis exercises its option for AKCEA-APOCIII-L<sub>Rx</sub>, Novartis will pay Akcea a license fee equal to $150 million. In addition, for AKCEA-APO(a)-L<sub>Rx</sub>, Akcea is eligible to receive up to $675 million in milestone payments, including $25 million for the achievement of a development milestone, up to $290 million for the achievement of regulatory milestones and up to $360 million for the achievement of commercialization milestones. In addition, for AKCEA-APOCIII-L<sub>Rx</sub>, Akcea is eligible to receive up to $530 million in milestone payments, including $25 million for the achievement of a development milestone, up to $240 million for the achievement of regulatory milestones and up to $265 million for the achievement of commercialization milestones. Akcea is also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of AKCEA-APO(a)-L<sub>Rx</sub> and AKCEA-APOCIII-L<sub>Rx</sub>. Akcea will pay 50 percent of these license fees, milestone payments and royalties to us as a sublicense fee.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>In connection with Novartis&#8217; license of AKCEA-APO(a)-L<sub>Rx</sub>, Akcea and Novartis established a more definitive framework under which the companies would negotiate the co-commercialization of AKCEA-APO(a)-L<sub>Rx</sub> in selected markets. Included in this framework is an option by which Novartis could solely commercialize AKCEA-APO(a)-L<sub>Rx</sub> in exchange for Novartis paying Akcea increased commercial milestone payments based on sales of AKCEA-APO(a)-L<sub>Rx</sub>.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> Akcea may co-commercialize IONIS-APOCIII-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> if licensed and commercialized by Novartis in selected markets through its specialized sales force under terms and conditions to be negotiated with Novartis in the future.</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6 million shares of our common stock for $100 million in the first quarter of 2017. 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These programs represent opportunities for us and our technology. In some cases, we have funded these studies through support from our partners or disease advocacy groups and foundations. Our External Project Funding partners include the following:</font></div><div><br /></div></div><div style="background-color: #FFFFFF;"><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">CHDI Foundation</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">- </font>Through our development collaboration, CHDI provided financial and scientific support to our Huntington&#8217;s disease drug discovery program. W<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">e have reimbursed CHDI for its support of our Huntington&#8217;s disease program out of the payments we receive from Roche.</font></font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Cystic Fibrosis Foundation</font>- We received upfront funding from the Cystic Fibrosis Foundation to discover and advance a medicine for the treatment of cystic fibrosis. In exchange for this funding, we are obligated to pay the Cystic Fibrosis Foundation up to $18 million upon achieving specific regulatory and sales events if we advance a medicine under our collaboration.</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">The Ludwig Institute; Center for Neurological Studies- </font>We have a collaboration with the Ludwig Institute, the Center for Neurological Studies and researchers to discover and develop antisense medicines for ALS and other neurodegenerative diseases. Under this agreement, we agreed to pay the Ludwig Institute and the Center for Neurological Studies modest milestone payments and royalties on any antisense medicines resulting from the collaboration.</font></div></td></tr></table></div></div></div><div><br /></div><div style="background-color: #FFFFFF;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">In-Licensing Agreements</div></div><div style="background-color: #FFFFFF;"><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our in-licensing arrangements include:</font></div></div><div style="background-color: #FFFFFF;"><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">University of Massachusetts- </font>We have a license agreement with the University of Massachusetts under which we acquired an exclusive license to the University of Massachusetts&#8217; patent rights related to SPINRAZA. We paid the University of Massachusetts nominal amounts for license fees and milestone payments we received. We also pay a low single digit royalty on net sales of SPINRAZA.</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Cold Spring Harbor Laboratory-</font> We have a collaboration and license agreement with the Cold Spring Harbor Laboratory under which we acquired an exclusive license to the Cold Spring Harbor Laboratory&#8217;s patent rights related to SPINRAZA. We paid Cold Spring Harbor Laboratory nominal amounts for license fees and milestone payments we received in 2017 and a low single digit royalty on net sales of SPINRAZA. Additionally, we owe a low single digit royalty on future sales of SPINRAZA.</font></div></td></tr></table></div></div></div><div><br /></div></div><span></span>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Segment Information and Concentration of Business Risk<br></strong></div></th>
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<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">7. Segment Information and Concentration of Business Risk</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have two reportable segments Ionis Core and Akcea Therapeutics. </font>At December 31, 2018, we owned approximately 75 percent of Akcea.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> Segment income (loss) from operations includes revenue less operating expenses attributable to each segment.</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In our Ionis Core segment we are exploiting our antisense technology to generate a broad pipeline of first-in-class and/or best-in-class medicines for us and our partners. 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vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: top; width: 52%; background-color: #CCEEFF;"><div style="text-align: left; margin-left: 25.2pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; 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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for reporting segments including data and tables. Reportable segments include those that meet any of the following quantitative thresholds a) it's reported revenue, including sales to external customers and intersegment sales or transfers is 10 percent or more of the combined revenue, internal and external, of all operating segments b) the absolute amount of its reported profit or loss is 10 percent or more of the greater, in absolute amount of 1) the combined reported profit of all operating segments that did not report a loss or 2) the combined reported loss of all operating segments that did report a loss c) its assets are 10 percent or more of the combined assets of all operating segments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -URI http://asc.fasb.org/topic&amp;trid=2134510<br></p></div>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6809878288">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Employment Benefits<br></strong></div></th>
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<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">8. Employment Benefits</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have an employee 401(k) salary deferral plan, covering all employees. Employees could make contributions by withholding a percentage of their salary up to the IRS annual limit $18,500 and $24,500 in 2018 for employees under 50 years old and employees 50 years old or over, respectively. We made approximately $5.7 million, $3.0 million and $1.7 million in matching contributions for the years ended December 31, 2018, 2017 and 2016, respectively.</font></div><div><br /></div></div><span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for pension and other postretirement benefits.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -URI http://asc.fasb.org/topic&amp;trid=2235017<br></p></div>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6971180336">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Legal Proceedings<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">9. Legal Proceedings</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we evaluate the status of each legal matter and assess our potential financial exposure. If the potential loss from any legal proceeding is considered probable and the amount can be reasonably estimated, we accrue a liability for the estimated loss. Significant judgment is required to determine the probability of a loss and whether the amount of the loss is reasonably estimable. The outcome of any proceeding is not determinable in advance. As a result, the assessment of a potential liability and the amount of accruals recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the potential liability related to the legal proceeding, and may revise our estimates.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Gilead Litigation</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In August 2013, Gilead Sciences Inc. filed a suit in the U.S. District Court of Northern District of California related to U.S. Patent Nos. 7,105,499 and 8,481,712, which are jointly owned by Merck Sharp &amp; Dohme Corp. and Ionis Pharmaceuticals, Inc.&#160;In the suit Gilead asked the court to determine that Gilead&#8217;s activities do not infringe any valid claim of the named patents and that the patents are not valid. We and Merck Sharp &amp; Dohme Corp. filed our answer denying Gilead&#8217;s noninfringement and invalidity contentions, contending that Gilead&#8217;s commercial sale and offer for sale of sofosbuvir prior to the expiration of the &#8216;499 and &#8216;712 patents infringes those patents, and requesting monetary damages to compensate for such infringement. In the trial for this case held in March 2016, the jury upheld all <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">ten</font> of the asserted claims of the patents-in-suit. The jury then decided that we and Merck are entitled to <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">four percent of $5 </font>billion in past sales of sofosbuvir. Gilead has stated it would appeal the jury&#8217;s finding of validity. In the meantime, Gilead asserted <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">two </font>additional non-jury defenses: waiver and unclean hands. Although the judge rejected the waiver defense, she granted Gilead&#8217;s motion claiming that the patents are unenforceable against it under the doctrine of unclean hands. We believe this ruling is contrary to the relevant law and the facts of the case. Accordingly, in July 2016, together with Merck we appealed the decision to the Court of Appeals for the Federal Circuit. Gilead cross-appealed on the issue of validity. In April 2018, the Court of Appeals issued its ruling affirming the District Court&#8217;s finding of unenforceability based on unclean hands.&#160;Having upheld the ruling that the patents are unenforceable against Gilead, the court did not reach the question of validity. In September 2018, we filed a petition requesting a hearing before the Supreme Court, asserting that it was improper for the trial court to overturn the jury verdict on the basis of the equitable defense of unclean hands. In January 2019, the Supreme Court denied our petition. Under our agreement with Merck, Merck is responsible for the costs of this suit.</font></div><div><br /></div></div><span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The entire disclosure for legal proceedings, legal contingencies, litigation, regulatory and environmental matters and other contingencies.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 450<br> -URI http://asc.fasb.org/topic&amp;trid=2127136<br></p></div>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6809981984">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Quarterly Financial Data (Unaudited)<br></strong></div></th>
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<tr><th class="th"><div>Dec. 31, 2018</div></th></tr>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_QuarterlyFinancialInformationTextBlock', window );">Quarterly Financial Data (Unaudited)</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">10. Quarterly Financial Data (Unaudited)</div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following financial information reflects all normal recurring adjustments, which are, in the opinion of management, necessary for a fair statement of the results of the interim periods. Summarized quarterly data for the years ended December 31, 2018 and 2017 are as follows (in thousands, except per share data).</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2018 Quarters</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">First</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Second</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Third</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Fourth</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quarter</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; 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width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: top; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9.1pt; margin-left: 9.1pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income available to Ionis common stockholders</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8,964</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">124,972</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; 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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6817270432">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies (Policies)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2018</div></th></tr>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConsolidationPolicyTextBlock', window );">Basis of Presentation</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basis of Presentation</div><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals,&#160;Inc. (&#8220;we&#8221;, &#8220;us&#8221; or &#8220;our&#8221;) and the consolidated results of our majority-owned affiliate,&#160;Akcea Therapeutics, Inc., which we formed in December 2014. In July 2017, Akcea completed an initial public offering, or IPO, and therefore beginning in July 2017, we no longer own 100 percent of Akcea. </font>From the closing of Akcea&#8217;s IPO in July 2017 through mid-April 2018, we owned approximately 68 percent<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>of Akcea. In the second, third and fourth quarters of 2018, we received additional shares of Akcea&#8217;s stock related to our license of TEGSEDI and AKCEA-TTR-L<sub>Rx</sub> to Akcea, increasing our ownership percentage to approximately 75 percent. We reflected the increase in our ownership in these financial statements. In the first quarter of 2019, Akcea will pay us a $75 million sublicense fee in Akcea common stock, as a result of Novartis&#8217; license of AKCEA-APO(a)-L<sub>Rx</sub> in February 2019. We will receive 2.8 million shares of Akcea common stock for the sublicense fee. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Refer to the noncontrolling interest in Akcea section in this note for further information related to our accounting for our investment in Akcea.</font></font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerSharePolicyTextBlock', window );">Basic and Diluted Net Income (Loss) per Share</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Basic and Diluted Net Income (Loss) per Share</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Basic net income (loss) per share</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The calculation of total net income (loss) attributable to our common stockholders for 2018 and 2017 considered our net income for Ionis on a stand-alone basis plus our share of Akcea&#8217;s net loss for the period. During 2016, we owned 100 percent of Akcea. To calculate the portion of Akcea&#8217;s net loss attributable to our ownership for 2018 and 2017, we multiplied Akcea&#8217;s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our&#160;total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for 2018 and 2017.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our basic net income per share for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2018</font>, was calculated as follows (in thousands, except per share amounts):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2018</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueRecognitionPolicyTextBlock', window );">Revenue Recognition</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Revenue Recognition</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Adoption of New Revenue Recognition Accounting Standard (Topic 606)</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In May 2014, the FASB issued accounting guidance on the recognition of revenue from customers. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">This guidance supersedes the revenue recognition requirements we previously followed in Accounting Standards Codification, or ASC, Topic 605, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Revenue Recognition</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, or Topic 605, and created a new Topic 606, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Revenue from Contracts with Customers</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, or Topic 606. </font>Under Topic 606, an entity will recognize revenue when it transfers control of promised goods or services to customers in an amount that reflects what the entity expects to receive in exchange for the goods or services. Further, an entity will recognize revenue upon satisfying the performance obligation(s) under the related contract. We adopted Topic 606 on January 1, 2018 under the full retrospective approach, which required us to revise our prior period revenue. Under Topic 606, we were required to review all of our ongoing collaboration agreements in which we recognized revenue after January 1, 2016. We were required to assess what our revenue would have been for the period from January 1, 2016 to December 31, 2017 under Topic 606. As a result of this analysis, we determined that the cumulative revenue we would have recognized under Topic 606 decreased by $86.1 million. We recorded this amount as a cumulative adjustment to our accumulated deficit as of January 1, 2016 on our revised statement of stockholders&#8217; equity. 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border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">At December 31, 2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom;"><div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Commercial revenue:</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: left; text-indent: 8.85pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">SPINRAZA royalties</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research and development revenue under collaborative agreements</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">325,898</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24,111</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; 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font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Under Topic 606, compared to Topic 605, our total revenue increased $6.5 million for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2017</font> and $26.2 million for <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2016</font>. 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When we made a change to our estimated completion period, we recognized that change on a prospective basis. Under Topic 606, we are required to use an input method to determine the amount we amortize each reporting period. Each period we review our &#8220;inputs&#8221; such as our level of effort expended, including the time we estimate it will take us to complete the activities or costs incurred, relative to the total expected inputs to satisfy the performance obligation. For certain collaborations, such as Bayer and Novartis, the input method resulted in a change to the revenue we had previously recognized using a straight-line amortization method.</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">This change resulted in a decrease in our R&amp;D revenue of $15.1 million for 2017. This change did not result in an impact to our 2016 R&amp;D revenue.</font></font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our updated revenue recognition policy reflecting Topic 606 is as follows:</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Our Revenue Sources</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue, we include the amounts in deferred revenue on our consolidated balance sheet.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as commercial revenue future sales milestone payments and royalties we earn under our partnerships.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Commercial Revenue: TEGSEDI Product Sales, net</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We began adding product sales from TEGSEDI to our commercial revenue in the fourth quarter of 2018. </font>In the U.S., TEGSEDI is distributed through an exclusive distribution agreement with a third-party logistics company, or 3PL, that takes title to TEGSEDI. The 3PL is our sole customer in the U.S. The 3PL then distributes TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distribute TEGSEDI to health care providers and patients. In Germany, TEGSEDI is distributed through a non-exclusive distribution model with a 3PL that takes title to TEGSEDI. The 3PL is our sole customer in Germany. The 3PL in Germany then distributes TEGSEDI to hospitals and pharmacies.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Research and development revenue under collaborative agreements</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&amp;D, services, and manufacturing services.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our collaboration agreements are detailed in Note 6, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements.</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160;</font>Under each collaboration note we discuss our specific revenue recognition conclusions, including our significant performance obligations under each collaboration.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Steps to Recognize Revenue</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use a five step process to determine the amount of revenue we should recognize and when we should recognize it. The five step process is as follows:</font></div><div><br /></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">1.</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Identify the contract</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the following criteria:</font></div><div><br /></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We and our partner approved the contract and we are both committed to perform our obligations;</font></div></td></tr></table></div></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have identified our rights, our partner&#8217;s rights and the payment terms;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the contract; and</font></div></td></tr></table></div></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We believe collectability is probable.</font></div></td></tr></table></div></div><div style="margin-bottom: 10pt;"><br /></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">2.</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Identify the performance obligations</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We next identify the distinct goods and services we are required to provide under the contract. Accounting rules refer to these as our performance obligations. We typically have only one performance obligation at the inception of a contract, which is to perform R&amp;D services.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Often times we enter into a collaboration agreement in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights. These items are contingent upon future events that may not occur. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation.</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">3.</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Determine the transaction price</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because the payments are not probable. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and are usually based on scientific progress. For example, in the first quarter of 2019, we earned a $35 million milestone payment from Roche when it dosed the first patient in the Phase 3 study of IONIS-HTT<sub>Rx</sub>.&#160; At December 31, 2018, we determined it was not probable that we could earn this milestone payment.&#160;As such, we did not recognize any revenue associated with it in 2018.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">&#160; &#160;</font></font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">4.</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Allocate the transaction price</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling price.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement. We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected income to present value. The significant inputs we use to determine the projected income of a license could include:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Estimated future product sales;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Estimated royalties on future product sales;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Contractual milestone payments;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Expenses we expect to incur;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Income taxes; and</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A discount rate.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We typically estimate the selling price of R&amp;D services by using our internal estimates of the cost to perform the specific services. The significant inputs we use to determine the selling price of our R&amp;D services include:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The number of internal hours we estimate we will spend performing these services;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of work we will perform;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of work that we will contract with third parties to perform; and</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The estimated cost of API we will use.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For purposes of determining the stand-alone selling price of the R&amp;D services we perform and the API we will deliver, accounting guidance requires us to include a markup for a reasonable profit margin.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">5.</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Recognize revenue</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&amp;D services. We recognize revenue at a point in time when our partner receives full use of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For R&amp;D services that we recognize over time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">change over the course of the collaboration, they may affect the timing and amount of revenue that we recognize in the current and future periods.</font></font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following are examples of when we typically recognize revenue based on the types of payments we receive.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize royalty revenue in the period in which the counterparty sells the related product, which in certain cases may require us to estimate our royalty revenue. </font>We recognize royalties from SPINRAZA sales in the period Biogen records the sale of SPINRAZA. Our accounting for SPINRAZA royalties did not change as a result of adopting Topic 606.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Commercial Revenue: TEGSEDI Product Sales, net</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize TEGSEDI product sales in the period </font>when our customer obtains control of TEGSEDI, which occurs at a point in time upon transfer of title to the customer. We classify payments to customers or other parties in the distribution channel for services that are distinct and priced at fair value as selling, general and administrative expenses in our consolidated statements of operations. Otherwise payments to customers or other parties in the distribution channel that do not meet those criteria are classified as a reduction of revenue, as discussed further below. We exclude from revenues, taxes collected from customers relating to product sales and remitted to governmental authorities.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Reserves for TEGSEDI Product Sales</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We record TEGSEDI product sales at our net sales price, or transaction price. We include in our transaction price estimated reserves for discounts, returns, chargebacks, rebates, co-pay assistance and other allowances that we offer within contracts between us and our customers, wholesalers, health care providers and other indirect customers. We estimate our reserves using the amounts we have earned or what we can claim on the associated sales. We classify our reserves as reductions of accounts receivable when the amount is payable to our customer or a current liability when the amount is payable to a party other than our customer in our consolidated balance sheet. In certain cases, our estimates include a range of possible outcomes that are probability-weighted for relevant factors such as our historical experience, current contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflect our best estimates under the terms of our respective contracts. When calculating our reserves and related product sales, we only recognize amounts to the extent that we consider it probable that we would not have to reverse in a future period a significant amount of the cumulative sales we previously recognized. The actual amounts we receive may ultimately differ from our reserve estimates. If actual amounts in the future vary from our estimates, we will adjust these estimates, which would affect our net TEGSEDI product sales in the respective period.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following are the components of variable consideration related to TEGSEDI product sales:</font></div><div><br /></div><div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Chargebacks: </font>In the U.S., we estimate obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charges us for the difference between what it pays for the product and the selling price to the qualified healthcare providers. We record reserves for these chargebacks related to TEGSEDI product sales to our U.S. customer during the reporting period. We also estimate the amount of product remaining in the distribution channel inventory at the end of the reporting period that we expect our customer to sell to wholesalers in future periods.</font></div><div><br /></div><div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Government rebates</font>: We are subject to discount obligations under government programs, including Medicaid programs and Medicare in the U.S. We estimate Medicaid and Medicare rebates based on a range of possible outcomes that are probability-weighted for the estimated payer mix. We record these reserves as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales in the same period we recognize the related sale. For Medicare rebates, we also estimate the number of patients in the prescription drug coverage gap for whom we will owe an additional liability under the Medicare Part D program. On a quarterly basis, we update our estimates and record any adjustments in the period that we identify the adjustments. In Germany, pharmaceutical companies must grant a specified rebate percentage to the German government. We include this rebate in the same period we recognize the related TEGSEDI product sales, resulting in a reduction of product sales.</font></div><div><br /></div><div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Trade discounts and allowances: </font>We provide customary invoice discounts on TEGSEDI product sales to our U.S. customer for prompt payment. We record this discount as a reduction of TEGSEDI product sales in the period in which we recognize the related product revenue. In addition, we receive and pay for various distribution services from our U.S. customer and wholesalers in our U.S. distribution channel. For services we receive that are either not distinct from the sale of TEGSEDI or for which we cannot reasonably estimate the fair value, we classify such fees as a reduction of TEGSEDI product sales.</font></div><div><br /></div><div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Product Returns: </font>Our U.S. customer has return rights and the wholesalers have limited return rights primarily related to the expiration date of the TEGSEDI product. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We estimate the amount of TEGSEDI product sales that our customer may return. We record our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale. Based on our distribution model for TEGSEDI, contractual inventory limits with our customer and wholesalers and the price of TEGSEDI, we believe we will have minimal returns. Our customer in Germany only takes title to the product once it receives an order from a hospital or pharmacy and therefore does not maintain any inventory of TEGSEDI, as such we do not estimate returns in Germany.</font></div><div><br /></div><div style="text-align: justify; margin-left: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Other incentives: </font>In the U.S., we estimate reserves for other incentives including co-payment assistance we provide to patients with commercial insurance who have coverage and reside in states that allow co-payment assistance. We record a reserve for the amount we estimate we will pay for co-payment assistance. We base our reserve on the number of estimated claims and our estimate of the cost per claim related to TEGSEDI product sales that we have recognized as revenue. We record our other incentive reserve estimates as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our TEGSEDI product sales, in the same period we recognize the related sale.</font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Research and development revenue under collaboration agreements:</u></font></div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Upfront Payments</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">When we enter into a collaboration agreement with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&amp;D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&amp;D services. For example, under our new <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">collaboration agreement with Roche to</font><font style="background-color: #FBFBFB; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> develop IONIS-FB-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;for the treatment of complement-mediated diseases</font>, we received a $75 million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our single performance obligation, R&amp;D services. We are amortizing the $75 million upfront payment using an input method over the estimated period of time we are providing R&amp;D services. Refer to <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font>, for further discussion. Under Topic 605, we amortized upfront payments evenly over the period of our obligation.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>Milestone Payments</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are required to include additional consideration in the transaction price when it is probable. We typically include milestone payments for R&amp;D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because there is considerable uncertainty in the research and development processes that trigger these payments under our collaboration agreements. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales based milestone payments in the period we achieve the milestone under the sales-based royalty exception allowed under accounting rules.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For example, in the third quarter of 2017, we initiated a Phase 1/2a clinical study of IONIS-MAPT<sub>Rx </sub>in patients with mild Alzheimer&#8217;s disease. We earned a $10 million milestone payment from Biogen related to the initiation of this study. Under Topic 606, we added this payment to the transaction price and allocated it to our R&amp;D services performance obligation. We are recognizing revenue from this milestone payment over our estimated period of performance. Under Topic 605, this milestone payment was recognized in full in the third quarter of 2017, which was the period in which we achieved the milestone event.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Conversely, we recognize in full those milestone payments that we earn based on our partners&#8217; activities when our partner achieves the milestone event. For example, in the third quarter of 2018, we recognized a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of IONIS-AZ4-2.5-L<sub>Rx</sub>. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We concluded that the milestone payment was not related to our R&amp;D services performance obligation. Therefore, we recognized this milestone payment in full in the third quarter of 2018 because we do not have any performance obligations related to this milestone payment. </font>Our revenue recognition of milestone payments we earn based on our partners&#8217; activities did not change as a result of adopting Topic 606.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-style: italic; font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><u>License Fees</u></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We generally recognize as revenue the total amount we determine to be the stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery. </font>For example, in the fourth quarter of 2018, we earned a $35 million license fee when Biogen licensed IONIS-SOD1<sub>Rx</sub> from us. Our recognition of license fees did not change as a result of adopting Topic 606.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Amendments to Agreements</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the accounting for the amendment:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If the goods and/or services are at a stand-alone selling price.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and at their stand-alone selling price, we then assess whether the remaining goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated revenue as a cumulative adjustment.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for the prevention of thrombosis. As part of the agreement, Bayer paid us a $100 million upfront payment. At the onset of the agreement, we were responsible for completing a Phase 2 study of IONIS-FXI</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and to initiate development of IONIS-FXI-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also eligible to receive milestone payments and tiered royalties on gross margins of IONIS-FXI</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> and IONIS-FXI-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of IONIS-FXI-L</font><sub>Rx</sub><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">, to provide R&amp;D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. </font>Refer to <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font>, for further discussion <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">of our accounting treatment for our Bayer collaboration. </font>Our allocation of the consideration we received for the Bayer amendment did not change as a result of adopting Topic 606. However, the method in which we are recognizing revenue related to our R&amp;D services performance obligation did change. We are amortizing revenue related to our R&amp;D services performance obligation using the input method under Topic 606.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Multiple Agreements</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the agreements were negotiated together with a single objective;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Whether the goods and/or services promised under the agreements are a single performance obligation.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance requires us to account for them as a combined arrangement.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: a new strategic neurology collaboration agreement and a stock purchase agreement, or SPA. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis. Refer to Note 6, </font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Collaborative Arrangements and Licensing Agreements</font><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> for further discussion of the accounting treatment for the 2018 strategic neurology collaboration with Biogen.</font></font></div><div><br /></div><div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Contracts Receivable</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our contracts receivable balance represents the amounts we have billed our partners for goods we have delivered or services we have performed that are due to us unconditionally. When we bill our partners with payment terms based on the passage of time, we consider the contract receivable to be unconditional. We typically receive payment within one quarter of billing our partner</font>. Our contracts receivable balance as of December 31, 2017 did not change when we adopted Topic 606.</font></div><div><br /></div><div style="text-align: justify; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Unbilled SPINRAZA Royalties</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet. </font>Our unbilled SPINRAZA royalties as of December 31, 2017 did not change when we adopted Topic 606.</font></div><div><br /></div><div style="text-align: left; text-indent: -18pt; margin-left: 54pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Deferred Revenue</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are often entitled to bill our customers and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet.</font> During the years ended December 31, 2018 and 2017, we recognized $105.3 million and $95.1 million of revenue from amounts that were in our beginning deferred revenue balances for those periods, respectively. 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vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 605</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Topic 606</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Adjustment</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Revised</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current portion of deferred contract revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">106,465</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">125,336</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term portion of deferred contract revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; 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width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,026</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"><div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total deferred revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">179,173</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">54,189</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">233,362</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td></tr></table><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our deferred revenue balance increased $54.2 million at December 31, 2017 under Topic 606, compared to Topic 605. The increase was primarily related to the change in the accounting for certain milestone payments and the way in which we amortize payments. Under Topic 605, we previously recognized the majority of the milestone payments we earned in the period we achieved the milestone event, which did not impact our deferred revenue balance. Under Topic 606 we are now amortizing more milestone payments over the period of our performance obligation, which adds to our deferred revenue balance. Additionally, under Topic 605 we amortized payments evenly over the period of our obligation. Under Topic 606, we are required to use an input method to determine the amount we amortize each reporting period. The increase in deferred revenue relates to agreements with the following partners:</div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$24.2 million from Biogen;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$15.9 million from AstraZeneca;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$11.8 million from Novartis; and</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#9679;</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$ 2.3 million from other partners.</font></div></td></tr></table></div></div><div><br /></div></div><span></span>
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<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CostOfProductsSoldPolicyTextBlock', window );">Cost of Products Sold</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cost of Products Sold</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We obtained the first regulatory approval for TEGSEDI in July 2018, as a result we began recognizing cost of products sold expenses related to TEGSEDI. Our cost of products sold includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the manufacturing and distribution of TEGSEDI. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of products sold. Prior to obtaining regulatory approval, we expensed a significant portion of the costs we incurred to produce the TEGSEDI supply we are using in the commercial launch as research and development expense.&#160; <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We previously recognized $0.1 million of costs to produce TEGSEDI related to the TEGSEDI commercial revenue we recognized in 2018.</font></font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpensePolicy', window );">Research and Development Expenses</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our research and development expenses include wages, benefits, facilities, supplies, external services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development services prior to the services being rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2018, 2017 and 2016, research and development expenses were $411.9 million, $372.5 million and $340.4 million, respectively. A portion of the costs included in research and development expenses are costs associated with our partner agreements. For the years ended December 31, 2018, 2017 and 2016, research and development costs of approximately $58.7 million, $59.5 million and $187.1 million, respectively, were related to our partner agreements.</div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IntangibleAssetsFiniteLivedPolicy', window );">Patent Expenses</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was 10.1 years at December 31, 2018.</div><div><br /></div><div style="text-align: left; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The cost of our patents capitalized on our consolidated balance sheet at December 31, 2018 and 2017 was $32.7 million and $30.8 million, respectively. Accumulated amortization related to patents was $8.7 million and $8.8 million at December 31, 2018 and 2017, respectively.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ending December 31,</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Amortization</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(in millions)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2019</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.7</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2020</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.6</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2021</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.5</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2022</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.4</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.3</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr></table><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications that have future value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2018, 2017 and 2016, patent expenses were $2.6 million, $2.1 million and $3.9 million, respectively, and included non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $0.8 million, $0.4 million and $2.3 million, respectively.</div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConsolidationSubsidiariesOrOtherInvestmentsConsolidatedEntitiesPolicy', window );">Noncontrolling Interest in Akcea Therapeutics, Inc.</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Noncontrolling Interest in Akcea Therapeutics, Inc.</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Prior to Akcea&#8217;s IPO in July 2017, we owned 100 percent of Akcea. From the closing of Akcea&#8217;s IPO in July 2017 through mid-April 2018, we owned approximately 68 percent<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font>of Akcea. In the second, third and fourth quarters of 2018, we received additional shares of Akcea&#8217;s stock related to our license of TEGSEDI and AKCEA-TTR-L<sub>Rx</sub> to Akcea, increasing our ownership percentage to approximately 75 percent. We reflected this increase in our ownership percentage in these financial statements as an adjustment to noncontrolling interest. <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The shares third parties own represent an interest in Akcea&#8217;s equity that is not controlled by us. However, as we continue to maintain overall control of Akcea through our voting interest, we reflect the assets, liabilities and results of operations of Akcea in our consolidated financial statements. We reflect the noncontrolling interest attributable to other owners of Akcea&#8217;s common stock in a separate line on the statement of operations and a separate line within stockholders&#8217; equity in our consolidated balance sheet. In addition, we record a noncontrolling interest adjustment to account for the stock options Akcea grants, which if exercised, will dilute our ownership in Akcea. This adjustment is a reclassification within stockholders&#8217; equity from additional paid-in capital to noncontrolling interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized.</font></font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskCreditRisk', window );">Concentration of Credit Risk</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Concentration of Credit Risk</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents, short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody&#8217;s, Standard&#160;&amp; Poor&#8217;s, or S&amp;P, or Fitch, respectively. We have established guidelines relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.</font></div><div><br /></div></div><span></span>
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<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CashCashEquivalentsAndInvestmentsPolicyTextBlock', window );">Cash, Cash Equivalents and Investments</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Cash, Cash Equivalents and Short-Term Investments</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents. Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as &#8220;available-for-sale&#8221; and carry them at fair market value based upon prices on the last day of the fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments. We use the specific identification method to determine the cost of securities sold.</font></div><div><br /></div><div style="background-color: #FFFFFF;"><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies that we received as part of a technology license or partner agreement. At December 31, 2018, we held equity investments in two publicly held companies, ProQR Therapeutics N.V., or ProQR, and Antisense Therapeutics Limited, or ATL. We also held equity investments in four privately-held companies, Atlantic Pharmaceuticals Limited, Dynacure SAS, Seventh Sense Biosystems and Suzhou Ribo Life Science Co, Ltd.</font></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2018, we adopted the amended accounting guidance related to the recognition, measurement, presentation, and disclosure of certain financial instruments. The amended guidance requires us to measure and record our equity investments at fair value. Additionally, the amended accounting guidance requires us to recognize the changes in fair value in our consolidated statement of operations, instead of through accumulated other comprehensive income. Prior to 2018, we accounted for our equity investments in privately held companies under the cost method of accounting. Under the amended guidance we account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer. Our adoption of this guidance did not have an impact on our results.</font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryPolicyTextBlock', window );">Inventory Valuation</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Inventory Valuation</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We reflect our inventory on our consolidated balance sheet at the lower of cost or market value under the first-in, first-out method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials they have alternative future uses. We include in inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and, as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We expense these costs as R&amp;D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency.</font></div><div style="text-align: justify;"><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We obtained the first regulatory approval for TEGSEDI in July 2018. At December 31, 2018, our physical inventory for TEGSEDI included API that we produced prior to when we obtained regulatory approval and accordingly has no cost basis as we had previously expensed the costs as R&amp;D expenses.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development and historical write-offs. We did not record any inventory write-offs for the years ended December 31, 2018, 2017 or 2016. Total inventory was $8.6 million and $10.0 million as of December 31, 2018 and 2017, respectively.</font></div><div><br /></div></div><span></span>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentPolicyTextBlock', window );">Property, Plant and Equipment</a></td>
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width: 64%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">179,141</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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font-family: 'Times New Roman', Times, serif;">(61,474</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(87,676</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Land</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,493</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,493</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;Total</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">132,160</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">121,907</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td></tr></table><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.</div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueOfFinancialInstrumentsPolicy', window );">Fair Value of Financial Instruments</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value of Financial Instruments</div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable, accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.</font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ImpairmentOrDisposalOfLongLivedAssetsIncludingIntangibleAssetsPolicyPolicyTextBlock', window );">Long-Lived Assets</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Long-Lived Assets</div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. We recorded charges of $0.8 million, $0.8 million and $2.3 million for the years ended December 31, 2018, 2017 and 2016, respectively, related primarily to the write-down of intangible assets.</font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UseOfEstimates', window );">Use of Estimates</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Use of Estimates</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The preparation of consolidated financial statements in conformity with accounting principles generally accepted in the U.S. requires management to make estimates and assumptions that affect the amounts reported in the consolidated financial statements and accompanying notes. Actual results could differ from those estimates.</font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationOptionAndIncentivePlansPolicy', window );">Stock-Based Compensation Expense</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Stock-Based Compensation Expense</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We measure stock-based compensation expense for equity-classified awards, principally related to stock options, restricted stock units, or RSUs, and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the requisite service period in our Consolidated Statements of Operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use the Black-Scholes model as our method of valuing option awards and stock purchase rights under our ESPP. On the grant date, we use our stock price and assumptions regarding a number of highly complex and subjective 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. Option-pricing models were developed for use in estimating the value of traded options that have no vesting or hedging restrictions and are fully transferable. Because our employee stock options have certain characteristics that are significantly different from traded options, and because changes in the subjective assumptions can materially affect the estimated value, in management&#8217;s opinion, the existing valuation models may not provide an accurate measure of the fair value of our employee stock options. Although we determine the estimated fair value of employee stock options using an option-pricing model, that value may not be indicative of the fair value observed in a willing buyer/willing seller market transaction.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We recognize compensation expense for option awards and RSUs 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.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The fair value of RSUs is based on the market price of our common stock on the date of grant.&#160;The RSUs we have granted vest annually over a four-year period.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">See Note 4, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Stockholders&#8217; Equity,</font> for additional information regarding our stock-based compensation plans.</font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityPolicyTextBlock', window );">Accumulated Other Comprehensive Loss</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Accumulated Other Comprehensive Loss</div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated other comprehensive loss is primarily comprised of unrealized gains and losses on investments, net of taxes and adjustments we made to reclassify realized gains and losses on investments from other accumulated comprehensive loss to our Consolidated Statement of Operations. 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padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Beginning balance accumulated other comprehensive loss</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;">(17,219</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Amounts reclassified from accumulated other comprehensive loss</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(374</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">447</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Currency translation adjustment</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(21</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net other comprehensive loss for the period</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(257</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,401</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; 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font-family: 'Times New Roman', Times, serif;">(1)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A tax benefit of $0.3 million was included in other comprehensive loss for the year ended December 31, 2018. 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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtPolicyTextBlock', window );">Convertible Debt</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Convertible Debt</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We account for convertible debt instruments, including our 1 percent and 2&#190; percent notes that may be settled in cash upon conversion (including partial cash settlement) by separating the liability and equity components of the instruments in a manner that reflects our nonconvertible debt borrowing rate. We determine the carrying amount of the liability component by measuring the fair value of similar debt instruments that do not have the conversion feature. If no similar debt instrument exists, we estimate fair value by using assumptions that market participants would use in pricing a debt instrument, including market interest rates, credit standing, yield curves and volatilities. We use accounting estimates and assumptions when we determine the fair value of the debt component. These estimates and assumptions we use are judgmental in nature and could have a significant impact on the determination of the debt component, and the associated non-cash interest expense.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We assigned a value to the debt component of our convertible notes equal to the estimated fair value of similar debt instruments without the conversion feature, which resulted in us recording our debt at a discount. We are amortizing our debt issuance costs and debt discount over the life of the convertible notes as additional non-cash interest expense utilizing the effective interest method. For additional information, see Note 3, <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Long-Term Obligations and Commitments</font>.</font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingPolicyPolicyTextBlock', window );">Segment Information</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Segment Information</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have two operating segments, our Ionis Core segment and Akcea Therapeutics, our majority-owned affiliate. Akcea is </font>a biopharmaceutical company focused on developing and commercializing medicines to treat patients with rare and serious diseases<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">. We provide segment financial information and results for our Ionis Core segment and our Akcea Therapeutics segment based on the segregation of revenues and expenses that our chief decision maker reviews to assess operating performance and to make operating decisions. We allocate a portion of Ionis&#8217; development, R&amp;D support and general and administrative expenses to Akcea for work Ionis performs on behalf of Akcea.</font></font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueMeasurementPolicyPolicyTextBlock', window );">Fair Value Measurements</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Fair Value Measurements</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity securities in publicly-held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify the majority of our securities as Level 2. We obtain the fair value of our Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and comparing that fair value to the fair value based on observable market prices. During 2018 and 2017, there were no transfers between our Level 1 and Level 2 investments. When we recognize transfers between levels of the fair value hierarchy, we recognize the transfer on the date the event or change in circumstances that caused the transfer occurs.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The following tables present the major security types we held at December 31, 2018 and 2017 that are regularly measured and carried at fair value. At December 31, 2018, our ProQR investment was <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">subject to trading restrictions through the fourth quarter of 2019, as a result we</font> included a lack of marketability discount in valuing this investment, which is a Level 3 input. At December 31, 2017, we did not have any financial instruments that we valued using Level 3 inputs. 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">276,612</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">93,932</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">994,798</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">117,080</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">877,718</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td></tr></table><div style="text-align: justify; text-indent: 500.1pt;"><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Included in cash and cash equivalents on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$50.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Included in short-term investments on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$14.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Included in other current assets on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(6)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$11.9 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(7)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$3.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-style: italic;">Novartis Future Stock Purchase</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In January 2017, we and Akcea entered into a SPA with Novartis. As part of the SPA, Novartis was required to purchase $50 million of Akcea&#8217;s common stock at the IPO price or our common stock at a premium if an IPO did not occur by April 2018. Therefore, at the inception of the SPA, we recorded a $5.0 million asset representing the fair value of the potential future premium we could have received if Novartis purchased our common stock. We determined the fair value of the future premium by calculating the value based on the stated premium in the SPA and estimating the probability of an Akcea IPO. We also included a <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">lack of marketability discount when we determined the fair value of the premium because we would have issued unregistered shares to Novartis if they had purchased our common stock. We measured this asset using Level 3 inputs and recorded it in other assets on our consolidated balance sheet. Because Akcea completed its IPO before April 2018, Novartis will not purchase additional shares of Ionis stock. Therefore, this asset no longer had any value and we wrote-off the remaining balance to other expenses on our third quarter 2017 consolidated statement of operations.</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following is a reconciliation of the potential premium we would have received if Akcea had not completed its IPO, measured at fair value on a recurring basis using significant unobservable inputs (Level 3) for 2017 (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31, 2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Beginning balance of Level 3 instruments</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Value of the potential premium we will receive from Novartis at inception of the SPA (January 2017)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5,035</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Write-off of premium to other expenses</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,035</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ending balance of Level 3 instruments</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td></tr></table><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxPolicyTextBlock', window );">Income Taxes</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Income Taxes</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development credit carryforwards. We record a valuation allowance when necessary to reduce deferred tax assets to the amount we expect to realize.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes. Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for income taxes in the period in which such determination is made.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted.<font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"> We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be realized.&#160;</font></font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">For U.S. federal income tax purposes, we are required to file separate U.S. federal income tax returns for Ionis and Akcea. We began deconsolidating Akcea for U.S. federal income tax purposes upon Akcea&#8217;s initial public offering. As a result, we are required to assess our Ionis stand-alone and Akcea&#8217;s valuation allowances separately even though we consolidate Akcea&#8217;s financial results in our consolidated financial statements. We continue to file combined state tax returns in most jurisdictions. As a result, we continue to assess the state portion of our valuation allowance for those jurisdictions on a consolidated basis.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We have historically recorded a valuation allowance against all our net deferred tax assets due to cumulative financial statement losses. However, in the fourth quarter of 2018, we reversed the valuation allowance previously recorded against our Ionis stand-alone U.S. federal net deferred tax assets, resulting in a one-time non-cash tax benefit of $332.1 million. Given our current stand-alone Ionis pre-tax income, and assuming we maintain this current level of Ionis stand-alone pre-tax income, we expect to generate income before taxes in the U.S. in future periods at a level that would result in us fully utilizing our U.S. federal net operating loss carryforwards and most of our Research and Development and Orphan Drug tax credit carryforwards over the next three years.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We continue to maintain a full valuation allowance of $234.2 million against all of Akcea&#8217;s net deferred tax assets and the net state deferred tax assets of Ionis at December 31, 2018 due to uncertainties related to our ability to realize the tax benefits associated with these assets.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries.</font></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NewAccountingPronouncementsPolicyPolicyTextBlock', window );">Impact of Recently Issued Accounting Standards</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">Impact of Recently Issued Accounting Standards</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2016, the FASB issued amended accounting guidance related to lease accounting, which will require us to record all leases with a term longer than one year on our balance sheet. When we record leases on our balance sheet under the new guidance, we will record a liability with a value equal to the present value of payments we will make over the life of the lease (lease liability) and an asset representing the underlying leased asset (right of use asset). The new accounting guidance requires us to determine if our leases are operating or financing leases. We will record expense for operating leases on a straight-line basis as an operating expense. If we determine a lease is a financing&#160;lease, we will record both interest and amortization expense and generally the expense will be higher in the earlier periods of the lease. We adopted this guidance on January 1, 2019 and adjusted our opening balance sheet on that date. We elected the available practical expedients. The most significant impact was the recognition of right of use assets and lease liabilities for our operating leases. We are in the process of finalizing the impact of the adoption. The adoption will not have an impact on our consolidated statement of operations or statement of cash flows.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 2016, the FASB issued guidance that changes the measurement of credit losses for most financial assets and certain other instruments. If we have credit losses, this updated guidance requires us to record allowances for these instruments under a new expected credit loss model. This model requires us to estimate the expected credit loss of an instrument over its lifetime, which represents the portion of the amortized cost basis we do not expect to collect. The new guidance requires us to remeasure our allowance in each reporting period we have credit losses. The new standard is effective for annual and interim periods beginning after December 15, 2019. Early adoption is permitted for periods beginning after December 15, 2018. When we adopt the new standard, we will make any adjustments to beginning balances through a cumulative-effect adjustment to accumulated deficit on that date. We plan to adopt this guidance on January 1, 2020. We are currently assessing the effects it will have on our consolidated financial statements and disclosures.</font></div><div style="text-align: justify;"><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In February 2018, the FASB issued updated guidance for reclassification of tax effects from accumulated other comprehensive income (loss). The updated guidance gives entities an option to reclassify amounts included in accumulated other comprehensive income (loss) that under the Tax Act do not have a way to be relieved, and allows a one-time reclassification to retained earnings. The updated guidance is effective for all entities for fiscal years beginning after December 31, 2018, and interim periods within those fiscal years. We have decided not to record the reclassification adjustments provided by this guidance.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In June 2018, the FASB issued updated guidance to simplify the accounting for stock-based compensation expense for nonemployees. Specifically, we are now expensing grants to nonemployees in a similar manner as grants to employees. Previously, we had to re-value these grants at each reporting period to reflect the current fair value. Under the amended guidance, we value grants to nonemployees when we grant them and we will not adjust their value for future changes. We adopted this guidance in the second quarter of 2018. The updated guidance did not have a material impact to our financial results.</font></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In November 2018, the FASB issued clarifying guidance of the interaction between the collaboration accounting guidance and the new revenue recognition guidance we adopted on January 1, 2018 (Topic 606). The clarifying guidance included the following:</font></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">When a participant is considered a customer in a collaborative arrangement, all of the associated accounting under Topic 606 should be applied;</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Adds &#8220;unit of account&#8221; concept to collaboration accounting guidance to align with Topic 606. This is used to determine if revenue is recognized or if a contra expense is recognized from consideration received under a collaboration; and</font></div></td></tr></table></div></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 36pt;"></td><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Precludes revenue from being recognized under Topic 606 when a transaction with a collaborative partner is determined not be a customer and is not directly related to the sales to third parties.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">The updated guidance is effective for public entities for fiscal years beginning after December 15, 2019, and interim periods within those fiscal years. Early adoption is permitted. We plan to adopt this guidance on January 1, 2020. We are currently assessing the effects it will have on our consolidated financial statements and disclosures.</font></div><div><br /></div></div><span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for cash, cash equivalents and investments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for recognizing cost of products sold expenses.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for credit risk.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy regarding (1) the principles it follows in consolidating or combining the separate financial statements, including the principles followed in determining the inclusion or exclusion of subsidiaries or other entities in the consolidated or combined financial statements and (2) its treatment of interests (for example, common stock, a partnership interest or other means of exerting influence) in other entities, for example consolidation or use of the equity or cost methods of accounting.  The accounting policy may also address the accounting treatment for intercompany accounts and transactions, noncontrolling interest, and the income statement treatment in consolidation for issuances of stock by a subsidiary.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for subsidiaries or other investments that are consolidated, including the accounting treatment for intercompany accounts or transactions and any noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section S99<br> -Paragraph 4<br> -Subparagraph (SX 210.3A-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=27015204&amp;loc=d3e355119-122828<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=d3e5614-111684<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18780-107790<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.3A-02)<br> -URI http://asc.fasb.org/extlink&amp;oid=27015204&amp;loc=d3e355033-122828<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section S99<br> -Paragraph 3<br> -Subparagraph (SX 210.3A-03)<br> -URI http://asc.fasb.org/extlink&amp;oid=27015204&amp;loc=d3e355100-122828<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<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(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy related to debt. Includes, but is not limited to, debt issuance costs, the effects of refinancings, method of amortizing debt issuance costs and original issue discount, and classifications of debt.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18780-107790<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6802200&amp;loc=d3e1835-112601<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for computing basic and diluted earnings or loss per share for each class of common stock and participating security. Addresses all significant policy factors, including any antidilutive items that have been excluded from the computation and takes into account stock dividends, splits and reverse splits that occur after the balance sheet date of the latest reporting period but before the issuance of the financial statements.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&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 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18780-107790<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3630-109257<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for fair value measurements of financial and non-financial assets, liabilities and instruments classified in shareholders' equity. Disclosures include, but are not limited to, how an entity that manages a group of financial assets and liabilities on the basis of its net exposure measures the fair value of those assets and liabilities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for determining the fair value of financial instruments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 60<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=7493716&amp;loc=d3e21868-110260<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13279-108611<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18780-107790<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for the impairment and disposal of long-lived assets including goodwill and other intangible assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ImpairmentOrDisposalOfLongLivedAssetsIncludingIntangibleAssetsPolicyPolicyTextBlock</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for income taxes, which may include its accounting policies for recognizing and measuring deferred tax assets and liabilities and related valuation allowances, recognizing investment tax credits, operating loss carryforwards, tax credit carryforwards, and other carryforwards, methodologies for determining its effective income tax rate and the characterization of interest and penalties in the financial statements.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32847-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 954<br> -SubTopic 740<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6491622&amp;loc=d3e9504-115650<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18780-107790<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 17<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32809-109319<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 19<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32840-109319<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 25<br> -URI http://asc.fasb.org/extlink&amp;oid=84176650&amp;loc=d3e32247-109318<br><br>Reference 7: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=84176650&amp;loc=d3e32280-109318<br><br>Reference 8: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 30<br> -Section 05<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=65884525&amp;loc=d3e40913-109327<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for finite-lived intangible assets. This accounting policy also might address: (1) the amortization method used; (2) the useful lives of such assets; and (3) how the entity assesses and measures impairment of such assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18780-107790<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of inventory accounting policy for inventory classes, including, but not limited to, basis for determining inventory amounts, methods by which amounts are added and removed from inventory classes, loss recognition on impairment of inventories, and situations in which inventories are stated above cost.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=66092785&amp;loc=d3e4556-108314<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18780-107790<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 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6361739&amp;loc=d3e7789-107766<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 270<br> -SubTopic 10<br> -Section 45<br> -Paragraph 6<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109236672&amp;loc=d3e543-108305<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=66092785&amp;loc=d3e4492-108314<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 210.5-02.6(b))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy pertaining to new accounting pronouncements that may impact the entity's financial reporting. Includes, but is not limited to, quantification of the expected or actual impact.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for long-lived, physical assets used in the normal conduct of business and not intended for resale. Includes, but is not limited to, basis of assets, depreciation and depletion methods used, including composite deprecation, estimated useful lives, capitalization policy, accounting treatment for costs incurred for repairs and maintenance, capitalized interest and the method it is calculated, disposals and impairments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.13(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18780-107790<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for costs it has incurred (1) in a planned search or critical investigation aimed at discovery of new knowledge with the hope that such knowledge will be useful in developing a new product or service, a new process or technique, or in bringing about a significant improvement to an existing product or process; or (2) to translate research findings or other knowledge into a plan or design for a new product or process or for a significant improvement to an existing product or process.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18780-107790<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 730<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6420194&amp;loc=d3e21568-108373<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for revenue recognition. If the entity has different policies for different types of revenue transactions, the policy for each material type of transaction is generally disclosed. If a sales transaction has multiple element arrangements (for example, delivery of multiple products, services or the rights to use assets) the disclosure may indicate the accounting policy for each unit of accounting as well as how units of accounting are determined and valued. The disclosure may encompass important judgment as to appropriateness of principles related to recognition of revenue. The disclosure also may indicate the entity's treatment of any unearned or deferred revenue that arises from the transaction.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/otherTransitionRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18780-107790<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/otherTransitionRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18726-107790<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/otherTransitionRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=84158767&amp;loc=d3e18823-107790<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for segment reporting.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Disclosure of accounting policy for stock option and stock incentive plans. This disclosure may include (1) the types of stock option or incentive plans sponsored by the entity (2) the groups that participate in (or are covered by) each plan (3) significant plan provisions and (4) how stock compensation is measured, and the methodologies and significant assumptions used to determine that measurement.</p></div>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6710956640">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfEarningsPerShareBasicAndDilutedTableTextBlock', window );">Basic and Diluted Net Income Per Share</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We calculated our diluted net income per share for 2018 as follows <font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(in thousands except per share amounts):</font></div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31, 2018</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; 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</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfNewAccountingPronouncementsAndChangesInAccountingPrinciplesTextBlock', window );">Adjustments Made to Adopt New Revenue Accounting Guidance</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following tables summarize the adjustments we were required to make to amounts we originally reported in 2017 and 2016 to adopt Topic 606 (in thousands, except per share amounts):</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold; font-style: italic;">Consolidated Balance Sheet</font></div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">At December 31, 2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">As Previously</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Reported under</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,871</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">125,336</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Long-term portion of deferred contract revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,708</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">35,318</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">108,026</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"><div style="text-align: left; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total deferred revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">179,173</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">54,189</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">233,362</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td></tr></table><div><br /></div></div><span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleofFiniteLivedIntangibleAssetsFutureAmortizationExpenseTableTextBlock', window );">Amortization Expense for Patents</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ending December 31,</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Amortization</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(in millions)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2019</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.7</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2020</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.6</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2021</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.5</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2022</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.4</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.3</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr></table><div><br /></div></div><span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfAccruedLiabilitiesTableTextBlock', window );">Accrued Liabilities</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our accrued liabilities consisted of the following (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Clinical expenses</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,125</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">16,347</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -18pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">In-licensing expenses</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">12,298</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">33,790</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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: -18pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Other miscellaneous expenses</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13,938</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">16,481</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total accrued liabilities</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">48,361</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">66,618</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td></tr></table><div><br /></div></div><span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentTextBlock', window );">Property, Plant and Equipment</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Estimated Useful Lives</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(in years)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; 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text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Leasehold improvements</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5 to 15</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">18,981</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">179,141</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(61,474</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(87,676</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">117,667</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">107,414</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Land</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;">14,493</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14,493</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;Total</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; 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text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">121,907</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td></tr></table><div><br /></div></div><span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfAccumulatedOtherComprehensiveIncomeLossTableTextBlock', window );">Changes in Accumulated Other Comprehensive Income (Loss)</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Accumulated other comprehensive loss is primarily comprised of unrealized gains and losses on investments, net of taxes and adjustments we made to reclassify realized gains and losses on investments from other accumulated comprehensive loss to our Consolidated Statement of Operations. 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padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Beginning balance accumulated other comprehensive loss</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(31,759</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(30,358</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(13,565</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Unrealized losses on securities, net of tax (1)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(280</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(960</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(17,219</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Amounts reclassified from accumulated other comprehensive loss</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(374</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">447</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 18pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Currency translation adjustment</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">23</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(67</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(21</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Net other comprehensive loss for the period</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(257</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,401</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(16,793</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ending balance accumulated other comprehensive loss</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(32,016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(31,759</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(30,358</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr></table><div style="text-align: justify;"><font style="display: inline-block; text-indent: 0px; font-size: 1px; width: 522pt;">&#160;</font><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">A tax benefit of $0.3 million was included in other comprehensive loss for the year ended December 31, 2018. There was no tax benefit or expense for other comprehensive loss for the years ended December 31, 2017 or 2016.</font></div></td></tr></table></div></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueAssetsMeasuredOnRecurringBasisTextBlock', window );">Assets Measured at Fair Value on a Recurring Basis</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-size: 10pt; font-weight: bold;">At</div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31, 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Quoted Prices in</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Active Markets</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Level 1)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Significant Other</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Observable Inputs</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(Level 2)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Significant</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> Unobservable Inputs</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">146,281</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">647,461</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by U.S. government agencies (3)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">136,325</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">136,325</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by the U.S. Treasury (3)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,818</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">30,818</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by states of the U.S. and political subdivisions of the states (7)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">93,932</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">93,932</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -8.9pt; margin-left: 22.55pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">994,798</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">117,080</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">877,718</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td></tr></table><div style="text-align: justify; text-indent: 500.1pt;"><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Included in cash and cash equivalents on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$50.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(3)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Included in short-term investments on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(4)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$14.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Included in other current assets on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(6)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$11.9 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(7)</font></td><td style="width: auto; vertical-align: top; text-align: justify;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$3.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationTextBlock', window );">Reconciliation of Assets Measured at Fair Value on a Recurring Basis Using Significant Unobservable Inputs (Level 3)</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following is a reconciliation of the potential premium we would have received if Akcea had not completed its IPO, measured at fair value on a recurring basis using significant unobservable inputs (Level 3) for 2017 (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31, 2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Beginning balance of Level 3 instruments</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Value of the potential premium we will receive from Novartis at inception of the SPA (January 2017)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5,035</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Write-off of premium to other expenses</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,035</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Ending balance of Level 3 instruments</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td></tr></table><div><br /></div></div><span></span>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Investments (Tables)<br></strong></div></th>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentsClassifiedByContractualMaturityDateTableTextBlock', window );">Contract Maturity of Available-for-Sale Securities</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2018:</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">One year or less</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">77</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">After one year but within two years</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">20</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">After two years but within three and one half years</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">100</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr></table><div><br /></div></div><span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrealizedGainLossOnInvestmentsTableTextBlock', window );">Summary of Investments</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following is a summary of our investments (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31, 2018</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Cost </font>(1)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Gains</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Losses</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Fair Value</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Available-for-sale securities:</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Corporate debt securities (2)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">956,879</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,858</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">955,034</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 52%; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by U.S. government agencies</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">168,839</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(104</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">168,738</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by the U.S. Treasury (2)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">244,640</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">15</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(77</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">244,578</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 52%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Debt securities issued by states of the U.S. and political subdivisions of the states</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">63,572</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(323</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">63,249</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#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;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total securities with a maturity of one year or less</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,433,930</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">31</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2,362</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; 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background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; 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vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">908,536</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td></tr></table><div><br /></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1)</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">We hold our available-for-sale securities at amortized cost.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: left;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td style="width: 18pt; vertical-align: top; align: right;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(2)</font></td><td style="width: auto; vertical-align: top; text-align: left;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Includes investments classified as cash equivalents on our consolidated balance sheet.</font></div></td></tr></table></div></div><div><br /></div><div style="text-align: justify;"><div><table cellpadding="0" cellspacing="0" class="DSPFListTable" style="font-family: 'Times New Roman', Times, serif; 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</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfTemporaryImpairmentLossesInvestmentsTableTextBlock', window );">Temporarily Impaired Investments</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Investments we consider to be temporarily impaired at December 31, 2018 are as follows (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom; 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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments (Tables)<br></strong></div></th>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtTableTextBlock', window );">Convertible Notes</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">At December 31, 2018, we had a nominal amount of our 2&#190; percent convertible senior notes outstanding. 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We measured the fair values of the convertible notes outstanding based on quoted market prices, which is a Level 2 measurement:</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Fair value of outstanding notes</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; 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width: 76%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Carrying value of equity component</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">219,011</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">219,011</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr></table><div><br /></div></div><span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationFiscalYearMaturityScheduleTableTextBlock', window );">Maturity Schedules</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Annual debt and other obligation maturities, including fixed and determinable interest, at December 31, 2018 are as follows (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2019</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">22,067</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2020</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">9,330</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2021</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">694,774</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2022</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2,809</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">2023</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3,494</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Thereafter</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">68,108</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Subtotal</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">800,582</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Less: current portion</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(12,890</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Less: fixed and determinable interest</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(41,837</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Less: unamortized portion of debt discount</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(111,426</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Plus: Deferred rent</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4,960</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 88%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfFutureMinimumLeasePaymentsForCapitalLeasesTableTextBlock', window );">Future Minimum Payments Under Operating Leases</a></td>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity (Tables)<br></strong></div></th>
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</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfSharebasedCompensationRestrictedStockAndRestrictedStockUnitsActivityTableTextBlock', window );">RSU Activity</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes the RSU activity for the year ended December 31, 2018 (in thousands, except per share data):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Number of</font></div><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; 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width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(82</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; 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width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,246</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; padding-bottom: 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">50.20</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td></tr></table><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfEmployeeServiceShareBasedCompensationAllocationOfRecognizedPeriodCostsTextBlock', window );">Stock-Based Compensation Expense</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following table summarizes stock-based compensation expense for the years ended December 31, 2018, 2017 and 2016 (in thousands), which was allocated as follows and includes $44.3 million, $17.5 million and $10.1 million of stock-based compensation expense for Akcea employees in 2018, 2017 and 2016, respectively:</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Cost of products sold</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">160</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Research, development and patent</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">76,557</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">64,521</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">55,099</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Selling, general and administrative</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">54,595</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">21,454</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">17,009</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">131,312</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">85,975</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">72,108</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td></tr></table><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationLineItems', window );"><strong>Stockholders' Equity [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock', window );">Weighted-Average Assumptions for Stock Options</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">For the years ended December 31, 2018, 2017 and 2016, we used the following weighted-average assumptions in our Black-Scholes calculations:</div><div><br /></div><div style="text-align: justify; text-indent: 36pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-style: italic;">Employee Stock Options:</font></div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Risk-free interest rate</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfShareBasedPaymentAwardEmployeeStockPurchasePlanValuationAssumptionsTableTextBlock', window );">Weighted-Average Assumptions for ESPP</a></td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member]</a></td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationLineItems', window );"><strong>Stockholders' Equity [Abstract]</strong></a></td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfShareBasedPaymentAwardStockOptionsValuationAssumptionsTableTextBlock', window );">Weighted-Average Assumptions for Stock Options</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">In addition to our stock plans, Akcea has its own stock plan under which it grants options and RSUs and under which it derives its stock-based compensation expense. 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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6709541104">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2018</div></th></tr>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxDisclosureAbstract', window );"><strong>Income Taxes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfIncomeBeforeIncomeTaxDomesticAndForeignTableTextBlock', window );">Loss Before Income Tax (Benefit) Expense</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Loss before income tax (benefit) expense is comprised of (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">United States</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(69,576</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(5,289</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(57,466</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Foreign</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(6,580</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(11,474</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Loss before income tax (benefit) expense</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(76,156</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(16,763</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(57,466</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td></tr></table><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfComponentsOfIncomeTaxExpenseBenefitTableTextBlock', window );">Income Tax (Benefit) Expense</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Our income tax (benefit) expense was as follows (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Current:</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Federal</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">438</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(7,460</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,067</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">State</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(1,442</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,246</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1,867</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Foreign</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">374</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">234</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; 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font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; 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vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total deferred income tax (benefit) expense</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(290,511</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; 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</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfEffectiveIncomeTaxRateReconciliationTableTextBlock', window );">Reconciliation of Statutory to Effective Tax Rate</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: left; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The reconciliation between our effective tax rate on loss from continuing operations and the statutory U.S. tax rate is as follows (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="22" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(76,156</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">(16,763</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">)</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; 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</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfDeferredTaxAssetsAndLiabilitiesTableTextBlock', window );">Deferred Tax Assets and Liabilities</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">Significant components of our deferred tax assets and liabilities as of December 31, 2018 and 2017 are as follows (in thousands):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Year Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; 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vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #FFFFFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #FFFFFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 76%; background-color: #CCEEFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Deferred Tax Liabilities:</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; 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vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">468,702</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; 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text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 76%; padding-bottom: 4px; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Total net deferred tax assets and liabilities</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 double 4px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 4px; background-color: #FFFFFF;">&#160;</td></tr></table><div><br /></div></div><span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfUnrecognizedTaxBenefitsRollForwardTableTextBlock', window );">Gross Unrecognized Tax Benefits</a></td>
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font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#8212;</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; background-color: #FFFFFF;"><div style="text-align: justify; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; 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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of the components of income tax expense attributable to continuing operations for each year presented including, but not limited to: current tax expense (benefit), deferred tax expense (benefit), investment tax credits, government grants, the benefits of operating loss carryforwards, tax expense that results from allocating certain tax benefits either directly to contributed capital or to reduce goodwill or other noncurrent intangible assets of an acquired entity, adjustments of a deferred tax liability or asset for enacted changes in tax laws or rates or a change in the tax status of the entity, and adjustments of the beginning-of-the-year balances of a valuation allowance because of a change in circumstances that causes a change in judgment about the realizability of the related deferred tax asset in future years.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of the components of net deferred tax asset or liability recognized in an entity's statement of financial position, including the following: the total of all deferred tax liabilities, the total of all deferred tax assets, the total valuation allowance recognized for deferred tax assets.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of the reconciliation using percentage or dollar amounts of the reported amount of income tax expense attributable to continuing operations for the year to the amount of income tax expense that would result from applying domestic federal statutory tax rates to pretax income from continuing operations.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Tabular disclosure of income before income tax between domestic and foreign jurisdictions.</p></div>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6819807888">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2018</div></th></tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBiogenMember', window );">Biogen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; 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vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">263.1</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; 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</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember', window );">AstraZeneca [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#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: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">41.3</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">20</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">4</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr></table><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBayerMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#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: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5.0</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">67.1</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">5.4</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">13</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr></table><div><br /></div></div><span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember', window );">GSK [Member]</a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [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="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#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: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1.6</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">14.8</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">17.5</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">0</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; 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</td>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember', window );">Janssen Biotech, Inc. [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Janssen (in millions, except percentage amounts):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#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: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; 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vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">24.8</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">7</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr></table><div><br /></div></div><span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsRocheMember', window );">Roche [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">During the years ended December 31, 2018, 2017 and 2016, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):</div><div><br /></div><table cellpadding="0" cellspacing="0" style="font-family: 'Times New Roman', Times, serif; font-size: 10pt; width: 100%;"><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="10" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Years Ended December 31,</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;"><div style="text-align: left;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">&#160;</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;"> 2018</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2017</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; padding-bottom: 2px;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom; border-bottom: #000000 solid 2px;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2016</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; padding-bottom: 2px;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="2" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom;">&#160;</td><td colspan="6" valign="bottom" style="vertical-align: bottom;"><div style="text-align: center;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(as revised)</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom;">&#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: -27pt; margin-left: 27pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">R&amp;D revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">8.3</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">55.7</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">$</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #CCEEFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">10.7</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #CCEEFF;">&#160;</td></tr><tr><td valign="bottom" style="vertical-align: bottom; width: 64%; padding-bottom: 2px; background-color: #FFFFFF;"><div style="text-align: left; text-indent: -9pt; margin-left: 9pt;"><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">Percentage of total revenue</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">1</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">11</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td><td colspan="1" valign="bottom" style="vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;">&#160;</td><td colspan="1" valign="bottom" style="vertical-align: bottom; text-align: right; width: 9%; border-bottom: #000000 solid 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">3</font></div></td><td colspan="1" nowrap="nowrap" valign="bottom" style="text-align: left; vertical-align: bottom; width: 1%; padding-bottom: 2px; background-color: #FFFFFF;"><div><font style="font-size: 10pt; font-family: 'Times New Roman', Times, serif;">%</font></div></td></tr></table><div><br /></div></div><span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember', window );">Novartis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementsAndNonCollaborativeArrangementTransactionsDisclosureLineItems', window );"><strong>Collaborative Arrangements and Licensing Agreements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SchedulesOfConcentrationOfRiskByRiskFactorTextBlock', window );">Revenue from Collaborative Relationship</a></td>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Quarterly Financial Data (Unaudited) (Tables)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
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<tr><th class="th"><div>Dec. 31, 2018</div></th></tr>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ScheduleOfQuarterlyFinancialInformationTableTextBlock', window );">Quarterly Financial Data</a></td>
<td class="text"><div style="font-family: 'Times New Roman', Times, serif; font-size: 10pt;"><div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-size: 10pt;">The following financial information reflects all normal recurring adjustments, which are, in the opinion of management, necessary for a fair statement of the results of the interim periods. 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<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="1">6 Months Ended</th>
<th class="th" colspan="1">12 Months Ended</th>
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<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
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<th class="th"><div>Mar. 31, 2017</div></th>
<th class="th"><div>Jun. 30, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
<th class="th"><div>Mar. 01, 2019</div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
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<td class="text">&#160;<span></span>
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<td class="nump">2.8<span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of the sublicense fee to be paid in Akcea common stock as a result of Novartis licensing AKCEA-APO(a)-L.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
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<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>
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</div></td></tr>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember</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>
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<DOCUMENT>
<TYPE>XML
<SEQUENCE>62
<FILENAME>R30.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
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<html>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6821528704">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Basic and Diluted Net Income (Loss) per Share (Details) - USD ($)<br> $ / shares in Units, shares in Thousands, $ in Thousands</strong></div></th>
<th class="th" colspan="16">3 Months Ended</th>
<th class="th" colspan="1">6 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th" colspan="2"><div>Dec. 31, 2018</div></th>
<th class="th" colspan="2"><div>Sep. 30, 2018</div></th>
<th class="th" colspan="2"><div>Jun. 30, 2018</div></th>
<th class="th" colspan="2"><div>Mar. 31, 2018</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2017</div></th>
<th class="th" colspan="2"><div>Sep. 30, 2017</div></th>
<th class="th" colspan="2"><div>Jun. 30, 2017</div></th>
<th class="th" colspan="2"><div>Mar. 31, 2017</div></th>
<th class="th"><div>Jun. 30, 2017</div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="nump">$ 2.32<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.03)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.29)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.01)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.03)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.02)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2],[3]</sup></td>
<td class="num">$ (0.02)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">$ 0.07<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2.09<span></span>
</td>
<td class="nump">$ 0.15<span></span>
</td>
<td class="num">$ (0.50)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss)</a></td>
<td class="nump">$ 320,078<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (4,559)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (40,358)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (1,420)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (2,922)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (2,611)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (3,085)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 8,964<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 273,741<span></span>
</td>
<td class="nump">$ 346<span></span>
</td>
<td class="num">$ (60,400)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic', window );">Net income available to Ionis common stockholders</a></td>
<td class="nump">$ 319,694<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (4,563)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (37,932)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (1,212)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (3,124)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (1,976)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 8,964<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 276,868<span></span>
</td>
<td class="nump">$ 18,792<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic', window );">Shares used in computing basic net income per share (in shares)</a></td>
<td class="nump">137,699<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">137,346<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">128,712<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">125,330<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">124,818<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">124,370<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">122,861<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">132,320<span></span>
</td>
<td class="nump">124,016<span></span>
</td>
<td class="nump">120,933<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted', window );">Income available to Ionis common shareholders, plus assumed conversions</a></td>
<td class="nump">$ 330,439<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 8,964<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 276,868<span></span>
</td>
<td class="nump">$ 18,792<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan', window );">Shares issuable related to our ESPP (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6<span></span>
</td>
<td class="nump">4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding', window );">Shares used in computing diluted net income per share (in shares)</a></td>
<td class="nump">149,856<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">124,972<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">134,056<span></span>
</td>
<td class="nump">126,098<span></span>
</td>
<td class="nump">120,933<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDiluted', window );">Diluted net income per share (in dollars per share)</a></td>
<td class="nump">$ 2.21<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2],[4]</sup></td>
<td class="num">$ (0.03)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="num">$ (0.29)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="num">$ (0.01)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="num">$ (0.03)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="num">$ (0.02)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2],[3]</sup></td>
<td class="num">$ (0.02)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">$ 0.07<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2],[5],[6]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2.07<span></span>
</td>
<td class="nump">$ 0.15<span></span>
</td>
<td class="num">$ (0.50)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember', window );">2 3/4 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">2.75%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">2.75%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">2.75%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockOptionMember', window );">Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements', window );">Shares issuable related to stock-based compensation (in shares)</a></td>
<td class="nump">1,254<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1,674<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,216<span></span>
</td>
<td class="nump">1,619<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockMember', window );">Restricted Stock Awards [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements', window );">Shares issuable related to stock-based compensation (in shares)</a></td>
<td class="nump">636<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">377<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">514<span></span>
</td>
<td class="nump">459<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementBusinessSegmentsAxis=ions_IonisCoreMember', window );">Ionis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss)</a></td>
<td class="nump">$ 372,913<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 43,226<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 5,882<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 18,785<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 10,510<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 10,144<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 440,806<span></span>
</td>
<td class="nump">$ 110,776<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SaleOfStockPercentageOfOwnershipBeforeTransaction', window );">Percentage ownership</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">100.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">100.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss)</a></td>
<td class="num">$ (53,219)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (47,789)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (43,814)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (19,997)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (13,634)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (12,120)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (163,938)<span></span>
</td>
<td class="num">$ (91,984)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Common Stock [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_WeightedAverageNumberOfSharesOwnedInSubsidiary', window );">Weighted average shares owned in Akcea (in shares)</a></td>
<td class="nump">67,130<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">65,538<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">60,832<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">45,448<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">45,448<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">36,556<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">59,812<span></span>
</td>
<td class="nump">20,669<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="num">$ (0.79)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.73)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.72)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.44)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.30)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.33)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (2.74)<span></span>
</td>
<td class="num">$ (3.08)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss)</a></td>
<td class="num">$ (53,219)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (47,789)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (43,814)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (19,997)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (13,634)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (12,063)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (163,938)<span></span>
</td>
<td class="num">$ (63,638)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Preferred Stock [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAbstract', window );"><strong>Basic Net Income (Loss) per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockDividendRatePercentage', window );">Dividend rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertiblePreferredStockTermsOfConversion', window );">Conversion ratio</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">converted into common stock on a 1:1 basis<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_WeightedAverageNumberOfSharesOwnedInSubsidiary', window );">Weighted average shares owned in Akcea (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">5,651<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,748<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.01)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (1.80)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (57)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (28,346)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr><td colspan="21"></td></tr>
<tr><td colspan="21"><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">As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income (loss) per share calculation for each of the quarters in 2018 and for the third and fourth quarters of 2017 considered our net income for Ionis on a stand-alone basis plus our share of Akcea's net loss for the period. To calculate the portion of Akcea's net loss attributable to our ownership, we multiplied Akcea's loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">We computed net income (loss) per share independently for each of the quarters presented. Therefore, the sum of the quarterly net income (loss) per share will not necessarily equal the total for the year.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[3]</td>
<td style="vertical-align: top;" valign="top">Prior to Akcea's IPO in July 2017, we owned Akcea series A convertible preferred stock, which included a six percent cumulative dividend. Upon completion of Akcea's IPO in July 2017, our preferred stock was converted into common stock on a 1:1 basis. The preferred stock dividend was not paid at the IPO because the IPO was not a liquidation event or a change in control. During the three months ended September 30, 2017, Akcea used a two-class method to compute its net income (loss) per share because it had both common and preferred shares outstanding during the periods. The two-class method required Akcea to calculate its net income (loss) per share for each class of stock by dividing total distributable losses applicable to preferred and common stock, including the six percent cumulative dividend contractually due to series A convertible preferred shareholders, by the weighted-average of preferred and common shares outstanding during the requisite period. Since Akcea used the two-class method, accounting rules required us to include our portion of Akcea's net income (loss) per share for both Akcea's common and preferred shares that we owned in our calculation of basic and diluted net income (loss) per share for the three months ended September 30, 2017.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[4]</td>
<td style="vertical-align: top;" valign="top">For the three months ended December 31, 2018, we had net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[5]</td>
<td style="vertical-align: top;" valign="top">For the three months ended March 31, 2017, the calculation excluded the 1 percent and 2.75 percent notes because the effect on diluted earnings per share was anti-dilutive.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[6]</td>
<td style="vertical-align: top;" valign="top">For the three months ended March 31, 2017, we owned 100 percent of Akcea. As a result, we did not have to adjust our earnings per share calculation. For the three months ended March 31, 2017, we had net income. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods.</td>
</tr>
</table></td></tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of shares issuable related to employee stock purchase plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_IncrementalCommonSharesAttributableToEmployeeStockPurchasePlan</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_WeightedAverageNumberOfSharesOwnedInSubsidiary">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares owned in the subsidiary during the reporting period determined by relating the portion of time within a reporting period that shares have been owned to the total time in that period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_WeightedAverageNumberOfSharesOwnedInSubsidiary</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConvertiblePreferredStockTermsOfConversion">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Specific terms relevant to convertibility. Includes class of preferred stock and number of shares convertible into, exercise (or conversion) price or rates, dates relevant to conversion timing and events relevant to conversion. Describe also any beneficial conversion features. where convertible preferred stock with a nondetachable conversion feature is in-the-money at commitment date. For contingently convertible preferred stock, discuss the circumstances of the contingency, including the events or changes in circumstance that would cause the contingency to be met and any of the significant features necessary to understand the conversion rights and the timing of those rights. Include also an events or changes in circumstance, if any, that could adjust or change the contingency, conversion price, or number of shares, including significant terms of those changes.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21538-112644<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(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21521-112644<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(27))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21506-112644<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21475-112644<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period per each share of common stock or unit outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(19))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&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 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1337-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=109256448&amp;loc=d3e4984-109258<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 (SX 210.5-03(21))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<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> -URI http://asc.fasb.org/extlink&amp;oid=109234566&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 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1252-109256<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&amp;loc=SL114874048-224260<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=SL5780133-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareBasic</td>
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<td>us-gaap_</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 class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareDiluted">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period available to each share of common stock or common unit outstanding during the reporting period and to each share or unit that would have been outstanding assuming the issuance of common shares or units for all dilutive potential common shares or units outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=109256448&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 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1252-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<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(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&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 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109234566&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 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1337-109256<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(21))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&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 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(19))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&amp;loc=SL114874131-224263<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>num: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>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of share based payment arrangements using the treasury stock method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28A<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1500-109256<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements</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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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
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</tr>
<tr>
<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of profit or loss for the period, net of income taxes, which is attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<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 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&amp;loc=SL114874048-224260<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<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 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(18))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&amp;loc=SL114874131-224263<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 S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(20))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br><br>Reference 7: 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> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>
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<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after deduction of tax, noncontrolling interests, dividends on preferred stock and participating securities; of income (loss) available to common shareholders.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109234566&amp;loc=d3e22694-107794<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 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1377-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
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</tr>
<tr>
<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after deduction of tax, noncontrolling interests, dividends on preferred stock and participating securities, and addition from assumption of issuance of common shares for dilutive potential common shares; of income (loss) available to common shareholders.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1505-109256<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 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1377-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage rate used to calculate dividend payments on preferred stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of subsidiary's or equity investee's stock owned by parent company before stock transaction.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The average number of shares or units issued and outstanding that are used in calculating diluted EPS or earnings per unit (EPU), determined based on the timing of issuance of shares or units in the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&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 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1505-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of [basic] shares or units, after adjustment for contingently issuable shares or units and other shares or units not deemed outstanding, determined by relating the portion of time within a reporting period that common shares or units have been outstanding to the total time in that period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1448-109256<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
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<th class="th" colspan="1">1 Months Ended</th>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">108,026<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">567,359<span></span>
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<td class="nump">108,026<span></span>
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<td class="text">&#160;<span></span>
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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="top.Show.showAR( this, 'defref_us-gaap_RetainedEarningsAccumulatedDeficit', window );">Accumulated deficit</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(967,293)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,241,034)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(967,293)<span></span>
</td>
<td class="num">(1,241,034)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterest', window );">Noncontrolling interest in Akcea Therapeutics, Inc.</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">139,081<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">84,267<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">139,081<span></span>
</td>
<td class="nump">84,267<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Total stockholders' equity</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,187,160<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">365,280<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,187,160<span></span>
</td>
<td class="nump">365,280<span></span>
</td>
<td class="nump">$ 39,613<span></span>
</td>
<td class="nump">$ 200,790<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 91,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">599,674<span></span>
</td>
<td class="nump">514,179<span></span>
</td>
<td class="nump">372,776<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,782<span></span>
</td>
<td class="num">$ (18,572)<span></span>
</td>
<td class="num">$ (50,281)<span></span>
</td>
<td class="num">$ (3,301)<span></span>
</td>
<td class="num">(6,200)<span></span>
</td>
<td class="nump">$ 11,312<span></span>
</td>
<td class="nump">$ 6,450<span></span>
</td>
<td class="nump">$ 19,485<span></span>
</td>
<td class="num">(61,372)<span></span>
</td>
<td class="nump">31,047<span></span>
</td>
<td class="num">(20,160)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">302,735<span></span>
</td>
<td class="num">(20,365)<span></span>
</td>
<td class="num">(56,573)<span></span>
</td>
<td class="num">(10,812)<span></span>
</td>
<td class="num">(9,169)<span></span>
</td>
<td class="num">(7,493)<span></span>
</td>
<td class="num">(3,085)<span></span>
</td>
<td class="nump">8,964<span></span>
</td>
<td class="nump">214,985<span></span>
</td>
<td class="num">(10,783)<span></span>
</td>
<td class="num">(60,400)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">320,078<span></span>
</td>
<td class="num">(4,559)<span></span>
</td>
<td class="num">(40,358)<span></span>
</td>
<td class="num">(1,420)<span></span>
</td>
<td class="num">(2,922)<span></span>
</td>
<td class="num">(2,611)<span></span>
</td>
<td class="num">(3,085)<span></span>
</td>
<td class="nump">8,964<span></span>
</td>
<td class="nump">273,741<span></span>
</td>
<td class="nump">$ 346<span></span>
</td>
<td class="num">$ (60,400)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAndDiluted', window );">Net income (loss) per share, basic and diluted (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0.15<span></span>
</td>
<td class="num">$ (0.50)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfCashFlowsAbstract', window );"><strong>Consolidated Statements of Cash Flows [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">302,735<span></span>
</td>
<td class="num">$ (20,365)<span></span>
</td>
<td class="num">$ (56,573)<span></span>
</td>
<td class="num">(10,812)<span></span>
</td>
<td class="num">(9,169)<span></span>
</td>
<td class="num">$ (7,493)<span></span>
</td>
<td class="num">$ (3,085)<span></span>
</td>
<td class="nump">8,964<span></span>
</td>
<td class="nump">214,985<span></span>
</td>
<td class="num">$ (10,783)<span></span>
</td>
<td class="num">$ (60,400)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract', window );"><strong>Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInContractWithCustomerLiability', window );">Deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">494,254<span></span>
</td>
<td class="nump">30,182<span></span>
</td>
<td class="num">(85,306)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents at beginning of year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">129,630<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">84,685<span></span>
</td>
<td class="nump">129,630<span></span>
</td>
<td class="nump">84,685<span></span>
</td>
<td class="nump">128,797<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents at end of year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 278,820<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">129,630<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">278,820<span></span>
</td>
<td class="nump">129,630<span></span>
</td>
<td class="nump">84,685<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_CommercialMember', window );">Commercial Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">254,922<span></span>
</td>
<td class="nump">120,014<span></span>
</td>
<td class="nump">22,767<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_SPINRAZARoyaltiesMember', window );">SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">237,930<span></span>
</td>
<td class="nump">112,540<span></span>
</td>
<td class="nump">883<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember', window );">Licensing and Other Royalty Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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</td>
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</td>
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</td>
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</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">14,755<span></span>
</td>
<td class="nump">7,474<span></span>
</td>
<td class="nump">21,884<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">Research and Development Revenue Under Collaborative Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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</td>
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</td>
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</td>
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</td>
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</td>
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</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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</td>
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</td>
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</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">344,752<span></span>
</td>
<td class="nump">394,165<span></span>
</td>
<td class="nump">350,009<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract', window );"><strong>Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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</td>
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</td>
<td class="text">&#160;<span></span>
</td>
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</td>
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</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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</td>
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</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance', window );">Increase in revenue from amortization of milestone payments achieved under new revenue guidance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">23,700<span></span>
</td>
<td class="nump">24,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod', window );">Decrease in revenue from amortization of payments using input method under new revenue guidance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(15,100)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NewAccountingPronouncementOrChangeInAccountingPrincipleRetrospectiveAdjustmentsAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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</td>
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</td>
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</td>
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</td>
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</td>
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</td>
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</td>
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</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NewAccountingPronouncementOrChangeInAccountingPrincipleCumulativeEffectOfChangeOnEquityOrNetAssets1', window );">Cumulative effect of adoption on retained earnings</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(86,100)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(86,100)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member] | As Previously Reported Under Topic 605 [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>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfFinancialPositionAbstract', window );"><strong>Consolidated Balance Sheet [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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</td>
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</td>
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</td>
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</td>
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</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityCurrent', window );">Current portion of deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">106,465<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">106,465<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityNoncurrent', window );">Long-term deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">72,708<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">72,708<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RetainedEarningsAccumulatedDeficit', window );">Accumulated deficit</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,187,398)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,187,398)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterest', window );">Noncontrolling interest in Akcea Therapeutics, Inc.</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">87,847<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>
<td class="nump">87,847<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Total stockholders' equity</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">418,719<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">418,719<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">507,666<span></span>
</td>
<td class="nump">346,620<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">24,534<span></span>
</td>
<td class="num">(46,316)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(17,296)<span></span>
</td>
<td class="num">(86,556)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (5,970)<span></span>
</td>
<td class="num">$ (86,556)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAndDiluted', window );">Net income (loss) per share, basic and diluted (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0.08<span></span>
</td>
<td class="num">$ (0.72)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfCashFlowsAbstract', window );"><strong>Consolidated Statements of Cash Flows [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (17,296)<span></span>
</td>
<td class="num">$ (86,556)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract', window );"><strong>Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInContractWithCustomerLiability', window );">Deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">36,695<span></span>
</td>
<td class="num">(59,150)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents at beginning of year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">129,630<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">84,685<span></span>
</td>
<td class="nump">129,630<span></span>
</td>
<td class="nump">84,685<span></span>
</td>
<td class="nump">128,797<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents at end of year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">129,630<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">129,630<span></span>
</td>
<td class="nump">84,685<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member] | As Previously Reported Under Topic 605 [Member] | Commercial Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">122,059<span></span>
</td>
<td class="nump">20,722<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member] | As Previously Reported Under Topic 605 [Member] | SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">112,540<span></span>
</td>
<td class="nump">883<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member] | As Previously Reported Under Topic 605 [Member] | Licensing and Other Royalty Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">9,519<span></span>
</td>
<td class="nump">19,839<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member] | As Previously Reported Under Topic 605 [Member] | Research and Development Revenue Under Collaborative Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">385,607<span></span>
</td>
<td class="nump">325,898<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member] | Topic 606 Adjustment [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfFinancialPositionAbstract', window );"><strong>Consolidated Balance Sheet [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityCurrent', window );">Current portion of deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">18,871<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">18,871<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityNoncurrent', window );">Long-term deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">35,318<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">35,318<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RetainedEarningsAccumulatedDeficit', window );">Accumulated deficit</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(53,636)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(53,636)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterest', window );">Noncontrolling interest in Akcea Therapeutics, Inc.</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(3,580)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(3,580)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Total stockholders' equity</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(53,439)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(53,439)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6,513<span></span>
</td>
<td class="nump">26,156<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6,513<span></span>
</td>
<td class="nump">26,156<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6,513<span></span>
</td>
<td class="nump">26,156<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 6,316<span></span>
</td>
<td class="nump">$ 26,156<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasicAndDiluted', window );">Net income (loss) per share, basic and diluted (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0.07<span></span>
</td>
<td class="nump">$ 0.22<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementOfCashFlowsAbstract', window );"><strong>Consolidated Statements of Cash Flows [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 6,513<span></span>
</td>
<td class="nump">$ 26,156<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract', window );"><strong>Adjustments to reconcile net income (loss) to net cash provided by (used in) operating activities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncreaseDecreaseInContractWithCustomerLiability', window );">Deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(6,513)<span></span>
</td>
<td class="num">(26,156)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents at beginning of year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsAtCarryingValue', window );">Cash and cash equivalents at end of year</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member] | Topic 606 Adjustment [Member] | Commercial Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(2,045)<span></span>
</td>
<td class="nump">2,045<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member] | Topic 606 Adjustment [Member] | SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member] | Topic 606 Adjustment [Member] | Licensing and Other Royalty Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(2,045)<span></span>
</td>
<td class="nump">2,045<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member', window );">Topic 606 [Member] | Topic 606 Adjustment [Member] | Research and Development Revenue Under Collaborative Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeStatementAbstract', window );"><strong>Consolidated Statements of Operations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 8,558<span></span>
</td>
<td class="nump">$ 24,111<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the effect of a change in accounting principle on revenue from the amortization of milestone payments achieved. The new revenue guidance requires the amortization of more of the milestone payments achieved, rather than recognizing the milestone payments in full during the period achieved.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfMilestonePaymentsAchievedUnderNewRevenueGuidance</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the effect of a change in accounting principle on revenue from the amortization of milestone payments achieved. The new revenue guidance requires the use of an input method to determine the amount amortized each reporting period rather than amortizing payments evenly over the period of obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NewAccountingPronouncementOrChangeInAccountingPrincipleEffectOfChangeOnRevenueFromAmortizationOfPaymentsUsingInputMethod</td>
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<tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of currency on hand as well as demand deposits with banks or financial institutions. Includes other kinds of accounts that have the general characteristics of demand deposits. Also includes short-term, highly liquid investments that are both readily convertible to known amounts of cash and so near their maturity that they present insignificant risk of changes in value because of changes in interest rates. Excludes cash and cash equivalents within disposal group and discontinued operation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3044-108585<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=82887183&amp;loc=d3e6676-107765<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.1)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashAndCashEquivalentsAtCarryingValue</td>
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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_ContractWithCustomerLiabilityCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable, classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiabilityCurrent</td>
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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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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiabilityNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable, classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiabilityNoncurrent</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareBasicAndDiluted">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income or loss for the period per each share in instances when basic and diluted earnings per share are the same amount and reported as a single line item on the face of the financial statements.  Basic earnings per share is the amount of net income or loss for the period per each share of common stock or unit outstanding during the reporting period.  Diluted earnings per share includes the amount of net income or loss for the period available to each share of common stock or common unit outstanding during the reporting period and to each share or unit that would have been outstanding assuming the issuance of common shares or units for all dilutive potential common shares or units outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1337-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EarningsPerShareBasicAndDiluted</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>num:perShareItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeStatementAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncreaseDecreaseInContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>
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<tr>
<td><strong> Balance Type:</strong></td>
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</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_MinorityInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total of all stockholders' equity (deficit) items, net of receivables from officers, directors, owners, and affiliates of the entity which is directly or indirectly attributable to that ownership interest in subsidiary equity which is not attributable to the parent (that is, noncontrolling interest, previously referred to as minority interest).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(24))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&amp;loc=d3e572229-122910<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.31)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=6876686&amp;loc=d3e534808-122878<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MinorityInterest</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_NetIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of profit or loss for the period, net of income taxes, which is attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<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 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&amp;loc=SL114874048-224260<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<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 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(18))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&amp;loc=SL114874131-224263<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 S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(20))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br><br>Reference 7: 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> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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_NewAccountingPronouncementOrChangeInAccountingPrincipleCumulativeEffectOfChangeOnEquityOrNetAssets1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cumulative effect of the change in accounting principle or new accounting pronouncement on retained earnings or other components of equity or net assets in the statement of financial position as of the beginning of the earliest period presented.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=109234566&amp;loc=d3e22499-107794<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=109234566&amp;loc=d3e22583-107794<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109234566&amp;loc=d3e22580-107794<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NewAccountingPronouncementOrChangeInAccountingPrincipleCumulativeEffectOfChangeOnEquityOrNetAssets1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_NewAccountingPronouncementOrChangeInAccountingPrincipleRetrospectiveAdjustmentsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NewAccountingPronouncementOrChangeInAccountingPrincipleRetrospectiveAdjustmentsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The net result for the period of deducting operating expenses from operating revenues.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingIncomeLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProfitLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (c)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4J<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591551-111686<br><br>Reference 7: 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 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3000-108585<br><br>Reference 8: 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 19<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4569616-111683<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8933-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4K<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591552-111686<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProfitLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RetainedEarningsAccumulatedDeficit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cumulative amount of the reporting entity's undistributed earnings or deficit.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(30)(a)(3))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(23)(a)(4))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&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 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=27012166&amp;loc=d3e187085-122770<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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_StatementOfCashFlowsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementOfCashFlowsAbstract</td>
</tr>
<tr>
<td style="padding-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_StatementOfFinancialPositionAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementOfFinancialPositionAbstract</td>
</tr>
<tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of stockholders' equity (deficit), net of receivables from officers, directors, owners, and affiliates of the entity, attributable to both the parent and noncontrolling interests. Amount excludes temporary equity. Alternate caption for the concept is permanent equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4568740-111683<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4I<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4590271-111686<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 15<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4568447-111683<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest</td>
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<th class="th" colspan="7">1 Months Ended</th>
<th class="th" colspan="1">2 Months Ended</th>
<th class="th" colspan="5">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
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<div>USD ($) </div>
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<div>Jul. 31, 2015 </div>
<div>USD ($) </div>
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<div>USD ($) </div>
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<div>USD ($) </div>
<div>PerformanceObligation</div>
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<div>Mar. 01, 2019 </div>
<div>USD ($)</div>
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<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
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<div>USD ($)</div>
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<div>Jun. 30, 2018 </div>
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<div>Sep. 30, 2017 </div>
<div>USD ($)</div>
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<th class="th">
<div>Jun. 30, 2015 </div>
<div>USD ($)</div>
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<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 14,755<span></span>
</td>
<td class="nump">7,474<span></span>
</td>
<td class="nump">21,884<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">344,752<span></span>
</td>
<td class="nump">394,165<span></span>
</td>
<td class="nump">350,009<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember', window );">Huntington's Disease [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember', window );">Huntington's Disease [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>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 35,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember', window );">IONIS-FB-L for Complement-Mediated Diseases [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember', window );">Neurology [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPriceAdditions', window );">Milestone payments received and added to transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember', window );">Cardiac, Renal and Metabolic Diseases [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 65,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 65,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember', window );">Cardiac, Renal and Metabolic Diseases [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember', window );">2013 Strategic Neurology [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember', window );">2013 Strategic Neurology [Member] | Licensing and Other Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">35,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember', window );">2013 Strategic Neurology [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 5,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBayerMember', window );">Bayer [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 5,000<span></span>
</td>
<td class="nump">$ 67,100<span></span>
</td>
<td class="nump">$ 5,400<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerAbstract', window );"><strong>Revenue Recognition [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentReceivedForAdvancingPrograms', window );">Payment received for advancing programs</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfAgreementsWithCollaborationPartner">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of agreements entered into with the collaboration partner.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfAgreementsWithCollaborationPartner</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PaymentReceivedForAdvancingPrograms">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of payments received during the period for advancing programs under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentReceivedForAdvancingPrograms</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PeriodAfterBillingWhenPaymentIsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The time period between billing a collaboration partner for goods delivered or services performed that are due unconditionally and payment is received from the collaboration partner, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PeriodAfterBillingWhenPaymentIsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPriceAdditions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The additional amount of consideration the Company earned under the collaboration agreement that is added to the transaction price.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPriceAdditions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_MajorCustomersAxis=ions_BiogenIncMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_MajorCustomersAxis=ions_BiogenIncMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember</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_SubsequentEventTypeAxis=us-gaap_SubsequentEventMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SubsequentEventTypeAxis=us-gaap_SubsequentEventMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember</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_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember</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_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember</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_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember</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_CollaborativeArrangementsAndLicensingAgreementsBayerMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember</td>
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<tr>
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<td><strong> Balance Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember</td>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6820135808">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Revenue Recognition - Deferred Revenue (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityAbstract', window );"><strong>Deferred Revenue [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityRevenueRecognized', window );">Revenue recognized</a></td>
<td class="nump">$ 105,300<span></span>
</td>
<td class="nump">$ 95,100<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityCurrent', window );">Current portion of deferred contract revenue</a></td>
<td class="nump">160,256<span></span>
</td>
<td class="nump">125,336<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityNoncurrent', window );">Long-term deferred contract revenue</a></td>
<td class="nump">$ 567,359<span></span>
</td>
<td class="nump">108,026<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Total deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">233,362<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis=us-gaap_CalculatedUnderRevenueGuidanceInEffectBeforeTopic606Member', window );">As Previously Reported Under Topic 605 [Member] | Topic 606 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityAbstract', window );"><strong>Deferred Revenue [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityCurrent', window );">Current portion of deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">106,465<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityNoncurrent', window );">Long-term deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">72,708<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Total deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">179,173<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis=us-gaap_DifferenceBetweenRevenueGuidanceInEffectBeforeAndAfterTopic606Member', window );">Topic 606 Adjustment [Member] | Topic 606 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityAbstract', window );"><strong>Deferred Revenue [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityCurrent', window );">Current portion of deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">18,871<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityNoncurrent', window );">Long-term deferred contract revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">35,318<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Total deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">54,189<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis=us-gaap_DifferenceBetweenRevenueGuidanceInEffectBeforeAndAfterTopic606Member', window );">Topic 606 Adjustment [Member] | Topic 606 [Member] | Biogen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityAbstract', window );"><strong>Deferred Revenue [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Total deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">24,200<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis=us-gaap_DifferenceBetweenRevenueGuidanceInEffectBeforeAndAfterTopic606Member', window );">Topic 606 Adjustment [Member] | Topic 606 [Member] | AstraZeneca [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityAbstract', window );"><strong>Deferred Revenue [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Total deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,900<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis=us-gaap_DifferenceBetweenRevenueGuidanceInEffectBeforeAndAfterTopic606Member', window );">Topic 606 Adjustment [Member] | Topic 606 [Member] | Novartis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityAbstract', window );"><strong>Deferred Revenue [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Total deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">11,800<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis=us-gaap_DifferenceBetweenRevenueGuidanceInEffectBeforeAndAfterTopic606Member', window );">Topic 606 Adjustment [Member] | Topic 606 [Member] | Other Partners [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiabilityAbstract', window );"><strong>Deferred Revenue [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Total deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2,300<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_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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_ContractWithCustomerLiabilityAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiabilityAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</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_ContractWithCustomerLiabilityCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable, classified as current.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiabilityCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiabilityNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable, classified as noncurrent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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_ContractWithCustomerLiabilityRevenueRecognized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of revenue recognized that was previously included in balance of obligation to transfer good or service to customer for which consideration from customer has been received or is due.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiabilityRevenueRecognized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_InitialApplicationPeriodCumulativeEffectTransitionAxis=us-gaap_CalculatedUnderRevenueGuidanceInEffectBeforeTopic606Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis=us-gaap_CalculatedUnderRevenueGuidanceInEffectBeforeTopic606Member</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AdjustmentsForNewAccountingPronouncementsAxis=us-gaap_AccountingStandardsUpdate201409Member</td>
</tr>
<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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</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis=us-gaap_DifferenceBetweenRevenueGuidanceInEffectBeforeAndAfterTopic606Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InitialApplicationPeriodCumulativeEffectTransitionAxis=us-gaap_DifferenceBetweenRevenueGuidanceInEffectBeforeAndAfterTopic606Member</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>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_MajorCustomersAxis=ions_BiogenIncMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_MajorCustomersAxis=ions_BiogenIncMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_MajorCustomersAxis=ions_AstraZenecaPLCMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_MajorCustomersAxis=ions_AstraZenecaPLCMember</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_srt_MajorCustomersAxis=ions_NovartisInternationalAGMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_MajorCustomersAxis=ions_NovartisInternationalAGMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_MajorCustomersAxis=ions_OtherPartnersMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_MajorCustomersAxis=ions_OtherPartnersMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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<TYPE>XML
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<TEXT>
<html>
<head>
<title></title>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6809863504">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Cost of Products Sold (Details)<br> $ in Millions</strong></div></th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CostOfGoodsAndServicesSoldAbstract', window );"><strong>Cost of Products Sold [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativeCostOfProductsSold', window );">Costs to produce TEGSEDI that were previously recognized</a></td>
<td class="nump">$ 0.1<span></span>
</td>
</tr>
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<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativeCostOfProductsSold">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cumulative costs related to goods produced and sold that were previously recognized as expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativeCostOfProductsSold</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_CostOfGoodsAndServicesSoldAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CostOfGoodsAndServicesSoldAbstract</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli: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>
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</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>67
<FILENAME>R35.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<body>
<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6820263632">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Research, Development and Patent Expenses (Details) - USD ($)<br> $ in Millions</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpenseAbstract', window );"><strong>Research, Development and Patent Expenses [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpense', window );">Research and development expenses</a></td>
<td class="nump">$ 411.9<span></span>
</td>
<td class="nump">$ 372.5<span></span>
</td>
<td class="nump">$ 340.4<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis=us-gaap_PatentsMember', window );">Patents [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PatentAbstract', window );"><strong>Patents [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetUsefulLife', window );">Estimated useful life</a></td>
<td class="text">10 years 1 month 6 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsGross', window );">Cost</a></td>
<td class="nump">$ 32.7<span></span>
</td>
<td class="nump">30.8<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization', window );">Accumulated amortization</a></td>
<td class="nump">8.7<span></span>
</td>
<td class="nump">8.8<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsFutureAmortizationExpenseAbstract', window );"><strong>Estimated Amortization Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths', window );">2019</a></td>
<td class="nump">1.7<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo', window );">2020</a></td>
<td class="nump">1.6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree', window );">2021</a></td>
<td class="nump">1.5<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="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour', window );">2022</a></td>
<td class="nump">1.4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive', window );">2023</a></td>
<td class="nump">1.3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PatentExpenses', window );">Patent expenses</a></td>
<td class="nump">2.6<span></span>
</td>
<td class="nump">2.1<span></span>
</td>
<td class="nump">3.9<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ImpairmentOfIntangibleAssetsFinitelived', window );">Non-cash charges related to write-down</a></td>
<td class="nump">0.8<span></span>
</td>
<td class="nump">0.4<span></span>
</td>
<td class="nump">2.3<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsMember', window );">Collaborative Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpenseAbstract', window );"><strong>Research, Development and Patent Expenses [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ResearchAndDevelopmentExpense', window );">Research and development expenses</a></td>
<td class="nump">$ 58.7<span></span>
</td>
<td class="nump">$ 59.5<span></span>
</td>
<td class="nump">$ 187.1<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PatentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PatentAbstract</td>
</tr>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<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_PatentExpenses">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Includes charges for amortization and write-downs of capitalized patent costs as well as legal fees for patent litigation and patent defense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PatentExpenses</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td><strong> Data Type:</strong></td>
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<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_FiniteLivedIntangibleAssetUsefulLife">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Useful life of finite-lived intangible assets, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetUsefulLife</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</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_FiniteLivedIntangibleAssetsAccumulatedAmortization">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Accumulated amount of amortization of assets, excluding financial assets and goodwill, lacking physical substance with a finite life.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>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_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense for assets, excluding financial assets and goodwill, lacking physical substance with a finite life expected to be recognized during the next fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense for assets, excluding financial assets and goodwill, lacking physical substance with a finite life expected to be recognized during the fifth fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense for assets, excluding financial assets and goodwill, lacking physical substance with a finite life expected to be recognized during the fourth fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense for assets, excluding financial assets and goodwill, lacking physical substance with a finite life expected to be recognized during the third fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense for assets, excluding financial assets and goodwill, lacking physical substance with a finite life expected to be recognized during the second fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_FiniteLivedIntangibleAssetsFutureAmortizationExpenseAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsFutureAmortizationExpenseAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<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_FiniteLivedIntangibleAssetsGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before amortization of assets, excluding financial assets and goodwill, lacking physical substance with a finite life.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 928<br> -SubTopic 340<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6473545&amp;loc=d3e61844-108004<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16323-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<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_ImpairmentOfIntangibleAssetsFinitelived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of impairment loss recognized in the period resulting from the write-down of the carrying amount of a finite-lived intangible asset to fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br><br>Reference 2: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 350<br> -SubTopic 30<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=66006027&amp;loc=d3e16373-109275<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ImpairmentOfIntangibleAssetsFinitelived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ResearchAndDevelopmentExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate costs incurred (1) in a planned search or critical investigation aimed at discovery of new knowledge with the hope that such knowledge will be useful in developing a new product or service, a new process or technique, or in bringing about a significant improvement to an existing product or process; or (2) to translate research findings or other knowledge into a plan or design for a new product or process or for a significant improvement to an existing product or process whether intended for sale or the entity's use, during the reporting period charged to research and development projects, including the costs of developing computer software up to the point in time of achieving technological feasibility, and costs allocated in accounting for a business combination to in-process projects deemed to have no alternative future use.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 985<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6501960&amp;loc=d3e128462-111756<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 730<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6420194&amp;loc=d3e21568-108373<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ResearchAndDevelopmentExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_ResearchAndDevelopmentExpenseAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ResearchAndDevelopmentExpenseAbstract</td>
</tr>
<tr>
<td style="padding-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_FiniteLivedIntangibleAssetsByMajorClassAxis=us-gaap_PatentsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis=us-gaap_PatentsMember</td>
</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_CollaborativeArrangementsAndLicensingAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsMember</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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<DOCUMENT>
<TYPE>XML
<SEQUENCE>68
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<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6972311888">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Accrued Liabilities (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract', window );"><strong>Organization and Significant Accounting Policies [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AccruedClinicalExpenses', window );">Clincial expenses</a></td>
<td class="nump">$ 22,125<span></span>
</td>
<td class="nump">$ 16,347<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AccruedInLicensingFeesCurrent', window );">In-licensing expenses</a></td>
<td class="nump">12,298<span></span>
</td>
<td class="nump">33,790<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherAccruedLiabilitiesCurrent', window );">Other miscellanous accruals</a></td>
<td class="nump">13,938<span></span>
</td>
<td class="nump">16,481<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccruedLiabilitiesCurrent', window );">Total accrued liabilities</a></td>
<td class="nump">$ 48,361<span></span>
</td>
<td class="nump">$ 66,618<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_AccruedClinicalExpenses">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of obligations incurred through that date and payable for clinical expenses. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AccruedClinicalExpenses</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of obligations incurred through that date and payable for in-licensing fees under collaboration agreements. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AccruedInLicensingFeesCurrent</td>
</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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying value as of the balance sheet date of obligations incurred and payable, pertaining to costs that are statutory in nature, are incurred on contractual obligations, or accumulate over time and for which invoices have not yet been received or will not be rendered. Examples include taxes, interest, rent and utilities. Used to reflect the current portion of the liabilities (due within one year or within the normal operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.20)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccruedLiabilitiesCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expenses incurred but not yet paid classified as other, due within one year or the normal operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.20)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=82887183&amp;loc=d3e6911-107765<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=82887183&amp;loc=d3e7018-107765<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=82887183&amp;loc=d3e6935-107765<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<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>69
<FILENAME>R37.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<body>
<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6800202048">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Noncontrolling Interest in Akcea Therapeutics, Inc. (Details) - Akcea [Member]<br></strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="1">6 Months Ended</th>
<th class="th" colspan="1">12 Months Ended</th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Mar. 31, 2017</div></th>
<th class="th"><div>Jun. 30, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Mar. 31, 2018</div></th>
<th class="th"><div>Jul. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOrSaleOfEquityAbstract', window );"><strong>Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SaleOfStockPercentageOfOwnershipBeforeTransaction', window );">Percentage ownership before IPO</a></td>
<td class="nump">100.00%<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterestOwnershipPercentageByParent', window );">Percentage ownership</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">75.00%<span></span>
</td>
<td class="nump">68.00%<span></span>
</td>
<td class="nump">68.00%<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_MinorityInterestOwnershipPercentageByParent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The parent entity's interest in net assets of the subsidiary, expressed as a percentage.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MinorityInterestOwnershipPercentageByParent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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_ProceedsFromIssuanceOrSaleOfEquityAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOrSaleOfEquityAbstract</td>
</tr>
<tr>
<td style="padding-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_SaleOfStockPercentageOfOwnershipBeforeTransaction">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of subsidiary's or equity investee's stock owned by parent company before stock transaction.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SaleOfStockPercentageOfOwnershipBeforeTransaction</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
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</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
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<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<body>
<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6972443600">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Cash, Cash Equivalents and Short-Term Investments (Details)<br></strong></div></th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>Company</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashCashEquivalentsAndShortTermInvestmentsAbstract', window );"><strong>Cash, Cash Equivalents and Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment', window );">Number of publicly-held companies in which there is an equity ownership interest of less than 20%</a></td>
<td class="nump">2<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment', window );">Number of privately-held companies in which there is an equity ownership interest of less than 20%</a></td>
<td class="nump">4<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of privately-held companies, in which the entity has an equity ownership interest of less than 20%, with which it conducts business. These are accounted for under the cost method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of publicly-held companies, in which the entity has an equity ownership interest of less than 20%, with which it conducts business. These are accounted for at fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CashCashEquivalentsAndShortTermInvestmentsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CashCashEquivalentsAndShortTermInvestmentsAbstract</td>
</tr>
<tr>
<td style="padding-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>
</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>71
<FILENAME>R39.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
							function toggleNextSibling (e) {
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<body>
<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6800260400">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Inventory Valuation (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryRawMaterialsAndSuppliesNetOfReservesAbstract', window );"><strong>Inventory Valuation [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryWriteDown', window );">Inventory write-off</a></td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InventoryNet', window );">Inventories</a></td>
<td class="nump">$ 8,582<span></span>
</td>
<td class="nump">$ 9,982<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_InventoryNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after valuation and LIFO reserves of inventory expected to be sold, or consumed within one year or operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=82887183&amp;loc=d3e6676-107765<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -SubTopic 10<br> -Section 35<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=68049868&amp;loc=d3e3927-108312<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.6(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InventoryNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InventoryRawMaterialsAndSuppliesNetOfReservesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InventoryRawMaterialsAndSuppliesNetOfReservesAbstract</td>
</tr>
<tr>
<td style="padding-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_InventoryWriteDown">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of loss from reductions in inventory due to subsequent measurement adjustments, including, but not limited to, physical deterioration, obsolescence, or changes in price levels.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -SubTopic 10<br> -Section 35<br> -Paragraph 1B<br> -URI http://asc.fasb.org/extlink&amp;oid=68049868&amp;loc=SL66093879-108312<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)<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&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 330<br> -SubTopic 10<br> -Section 35<br> -Paragraph 1C<br> -URI http://asc.fasb.org/extlink&amp;oid=68049868&amp;loc=SL66093883-108312<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 330<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=66092785&amp;loc=d3e4542-108314<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InventoryWriteDown</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>72
<FILENAME>R40.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
							function toggleNextSibling (e) {
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</head>
<body>
<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6804674128">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Property, Plant and Equipment (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment', window );">Less accumulated depreciation</a></td>
<td class="num">$ (61,474)<span></span>
</td>
<td class="num">$ (87,676)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentNet', window );">Property, plant and equipment, net</a></td>
<td class="nump">132,160<span></span>
</td>
<td class="nump">121,907<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_PropertyPlantAndEquipmentExcludingLandMember', window );">Property, Plant and Equipment, Excluding Land [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">179,141<span></span>
</td>
<td class="nump">195,090<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentNet', window );">Property, plant and equipment, net</a></td>
<td class="nump">117,667<span></span>
</td>
<td class="nump">107,414<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_EquipmentAndComputerSoftwareMember', window );">Computer Software, Laboratory, Manufacturing and Other Equipment [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 53,496<span></span>
</td>
<td class="nump">66,558<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_EquipmentAndComputerSoftwareMember', window );">Computer Software, Laboratory, Manufacturing and Other Equipment [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">3 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_EquipmentAndComputerSoftwareMember', window );">Computer Software, Laboratory, Manufacturing and Other Equipment [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">10 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_BuildingAndBuildingImprovementsMember', window );">Building, Building Improvements and Building Systems [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 97,528<span></span>
</td>
<td class="nump">92,770<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_BuildingAndBuildingImprovementsMember', window );">Building, Building Improvements and Building Systems [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">15 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_BuildingAndBuildingImprovementsMember', window );">Building, Building Improvements and Building Systems [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">40 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandImprovementsMember', window );">Land Improvements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 2,853<span></span>
</td>
<td class="nump">2,853<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">20 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LeaseholdImprovementsMember', window );">Leasehold Improvements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 18,981<span></span>
</td>
<td class="nump">26,748<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LeaseholdImprovementsMember', window );">Leasehold Improvements [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LeaseholdImprovementsMember', window );">Leasehold Improvements [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">15 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_FurnitureAndFixturesMember', window );">Furniture and Fixtures [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 6,283<span></span>
</td>
<td class="nump">6,161<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_FurnitureAndFixturesMember', window );">Furniture and Fixtures [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_FurnitureAndFixturesMember', window );">Furniture and Fixtures [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentUsefulLife', window );">Estimated useful lives</a></td>
<td class="text">10 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandMember', window );">Land [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentAbstract', window );"><strong>Property, Plant and Equipment [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentGross', window );">Property, plant and equipment</a></td>
<td class="nump">$ 14,493<span></span>
</td>
<td class="nump">$ 14,493<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of accumulated depreciation, depletion and amortization for physical assets used in the normal conduct of business to produce goods and services.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.14)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before accumulated depreciation, depletion and amortization of physical assets used in the normal conduct of business and not intended for resale. Examples include, but are not limited to, land, buildings, machinery and equipment, office equipment, and furniture and fixtures.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.13)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after accumulated depreciation, depletion and amortization of physical assets used in the normal conduct of business to produce goods and services and not intended for resale. Examples include, but are not limited to, land, buildings, machinery and equipment, office equipment, and furniture and fixtures.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(14))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 360<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6391035&amp;loc=d3e2868-110229<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(a)(8))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&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 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(13))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentUsefulLife">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Useful life of long lived, physical assets used in the normal conduct of business and not intended for resale, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days. Examples include, but not limited to, land, buildings, machinery and equipment, office equipment, furniture and fixtures, and computer equipment.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentUsefulLife</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_PropertyPlantAndEquipmentExcludingLandMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_PropertyPlantAndEquipmentExcludingLandMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_EquipmentAndComputerSoftwareMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_EquipmentAndComputerSoftwareMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_RangeAxis=srt_MinimumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MinimumMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_RangeAxis=srt_MaximumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MaximumMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_BuildingAndBuildingImprovementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_BuildingAndBuildingImprovementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandImprovementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandImprovementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LeaseholdImprovementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LeaseholdImprovementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_FurnitureAndFixturesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_FurnitureAndFixturesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_LandMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>73
<FILENAME>R41.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<body>
<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6972346256">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Long-Lived Assets (Details) - USD ($)<br> $ in Millions</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetImpairmentChargesAbstract', window );"><strong>Long-Lived Assets [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetImpairmentCharges', window );">Charges related to write-down of long-lived assets</a></td>
<td class="nump">$ 0.8<span></span>
</td>
<td class="nump">$ 0.8<span></span>
</td>
<td class="nump">$ 2.3<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_AssetImpairmentCharges">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of write-down of assets recognized in the income statement. Includes, but is not limited to, losses from tangible assets, intangible assets and goodwill.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&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 360<br> -SubTopic 10<br> -Section 45<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=109226348&amp;loc=d3e2420-110228<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AssetImpairmentCharges</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AssetImpairmentChargesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AssetImpairmentChargesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>74
<FILENAME>R42.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
							function toggleNextSibling (e) {
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<body>
<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6972184288">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Stock-Based Compensation Expense (Details)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th"><div>Dec. 31, 2018</div></th></tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember', window );">RSUs [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationAbstract', window );"><strong>Stock-Based Compensation [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">4 years<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_ShareBasedCompensationAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period which an employee's right to exercise an award is no longer contingent on satisfaction of either a service condition, market condition or a performance condition, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6802822784">
<tr>
<th class="tl" colspan="2" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Accumulated Other Comprehensive Loss (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract', window );"><strong>Accumulated Other Comprehensive Income (Loss) [Roll Forward]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 365,280<span></span>
</td>
<td class="nump">$ 39,613<span></span>
</td>
<td class="nump">$ 200,790<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeLossNetOfTax', window );">Net other comprehensive loss for the period</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(257)<span></span>
</td>
<td class="num">(1,401)<span></span>
</td>
<td class="num">(16,793)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,187,160<span></span>
</td>
<td class="nump">365,280<span></span>
</td>
<td class="nump">39,613<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeLossTax', window );">Income tax expense included in other comprehensive loss</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">300<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementEquityComponentsAxis=us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember', window );">Accumulated Other Comprehensive Loss [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract', window );"><strong>Accumulated Other Comprehensive Income (Loss) [Roll Forward]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(31,759)<span></span>
</td>
<td class="num">(30,358)<span></span>
</td>
<td class="num">(13,565)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest', window );">Balance</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(32,016)<span></span>
</td>
<td class="num">(31,759)<span></span>
</td>
<td class="num">(30,358)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementEquityComponentsAxis=us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember', window );">Unrealized Losses on Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract', window );"><strong>Accumulated Other Comprehensive Income (Loss) [Roll Forward]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax', window );">Other comprehensive loss before reclassifications, net of tax</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="num">(280)<span></span>
</td>
<td class="num">(960)<span></span>
</td>
<td class="num">(17,219)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTax', window );">Amounts reclassified from accumulated other comprehensive loss</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="num">(374)<span></span>
</td>
<td class="nump">447<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementEquityComponentsAxis=us-gaap_AccumulatedForeignCurrencyAdjustmentIncludingPortionAttributableToNoncontrollingInterestMember', window );">Currency Translation Adjustment [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract', window );"><strong>Accumulated Other Comprehensive Income (Loss) [Roll Forward]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax', window );">Other comprehensive loss before reclassifications, net of tax</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 23<span></span>
</td>
<td class="num">$ (67)<span></span>
</td>
<td class="num">$ (21)<span></span>
</td>
</tr>
<tr><td colspan="4"></td></tr>
<tr><td colspan="4"><table class="outerFootnotes" width="100%"><tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top">A tax benefit of $0.3 million was included in other comprehensive loss for the year ended December 31, 2018. There was no tax benefit or expense for other comprehensive loss for the years ended December 31, 2017 or 2016.</td>
</tr></table></td></tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax, before reclassification adjustments of other comprehensive income (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14A<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669686-108580<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 55<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=109228884&amp;loc=d3e1436-108581<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeLossBeforeReclassificationsNetOfTax</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax and reclassification adjustments of other comprehensive income (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 55<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=109228884&amp;loc=d3e1436-108581<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OtherComprehensiveIncomeLossNetOfTax</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of tax expense (benefit) allocated to other comprehensive income (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 11<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109238882&amp;loc=d3e39076-109324<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=109238882&amp;loc=d3e38679-109324<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 12<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=d3e640-108580<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount after tax of reclassification adjustments of other comprehensive income (loss).</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTax</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ReclassificationFromAccumulatedOtherComprehensiveIncomeCurrentPeriodNetOfTaxAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of stockholders' equity (deficit), net of receivables from officers, directors, owners, and affiliates of the entity, attributable to both the parent and noncontrolling interests. Amount excludes temporary equity. Alternate caption for the concept is permanent equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4568740-111683<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4I<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4590271-111686<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 15<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4568447-111683<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockholdersEquityIncludingPortionAttributableToNoncontrollingInterest</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StatementEquityComponentsAxis=us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementEquityComponentsAxis=us-gaap_AociIncludingPortionAttributableToNoncontrollingInterestMember</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>
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<td><strong> Balance Type:</strong></td>
<td></td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementEquityComponentsAxis=us-gaap_AccumulatedNetInvestmentGainLossIncludingPortionAttributableToNoncontrollingInterestMember</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_us-gaap_StatementEquityComponentsAxis=us-gaap_AccumulatedForeignCurrencyAdjustmentIncludingPortionAttributableToNoncontrollingInterestMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementEquityComponentsAxis=us-gaap_AccumulatedForeignCurrencyAdjustmentIncludingPortionAttributableToNoncontrollingInterestMember</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>
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<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6972315776">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Convertible Debt (Details)<br></strong></div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Mar. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermConvertibleDebtCurrentAndNoncurrentAbstract', 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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember', window );">2 3/4 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermConvertibleDebtCurrentAndNoncurrentAbstract', 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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LongtermConvertibleDebtCurrentAndNoncurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LongtermConvertibleDebtCurrentAndNoncurrentAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td>na</td>
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<tr>
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<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_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<td><strong> Period Type:</strong></td>
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<TYPE>XML
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<DESCRIPTION>IDEA: XBRL DOCUMENT
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<head>
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<link rel="stylesheet" type="text/css" href="report.css">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6972152176">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Segment Information (Details)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th">
<div>Dec. 31, 2018 </div>
<div>Segment</div>
</th></tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NumberOfOperatingSegments', window );">Number of operating segments</a></td>
<td class="nump">2<span></span>
</td>
</tr>
</table>
<div style="display: none;">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of operating segments. An operating segment is a component of an enterprise: (a) that engages in business activities from which it may earn revenues and incur expenses (including revenues and expenses relating to transactions with other components of the same enterprise), (b) whose operating results are regularly reviewed by the enterprise's chief operating decision maker to make decisions about resources to be allocated to the segment and assess its performance, and (c) for which discrete financial information is available. An operating segment may engage in business activities for which it has yet to earn revenues, for example, start-up operations may be operating segments before earning revenues.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NumberOfOperatingSegments</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli: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>duration</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
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</div></td></tr>
</table>
</div>
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<DOCUMENT>
<TYPE>XML
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<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
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<head>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6819797488">
<tr>
<th class="tl" colspan="2" rowspan="1"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Fair Value Measurements on a Recurring Basis (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2"><div>Dec. 31, 2018</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OrganizationConsolidationAndPresentationOfFinancialStatementsAbstract', window );"><strong>Organization and Significant Accounting Policies [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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueAssetsLevel1ToLevel2TransfersAmount', window );">Transfers from Level 1 to Level 2</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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueAssetsLevel2ToLevel1TransfersAmount', window );">Transfers from Level 2 to Level 1</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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,871,017<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>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsFairValueDisclosure', window );">Cash equivalents</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">146,281<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">86,262<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment in ProQR Therapeutics N.V.</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">1,349<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>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">2,017,298<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">994,798<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Corporate Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,252,960<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[3]</sup></td>
<td class="nump">647,461<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[4]</sup></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Corporate Debt Securities [Member] | Cash and Cash Equivalents [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">50,200<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">11,900<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Debt Securities issued by U.S. Government Agencies [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[5]</sup></td>
<td class="nump">276,612<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">136,325<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Debt Securities issued by the U.S. Treasury [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">260,154<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[6]</sup></td>
<td class="nump">30,818<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[5]</sup></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Debt Securities issued by the U.S. Treasury [Member] | 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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">14,200<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>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">79,942<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[5]</sup></td>
<td class="nump">93,932<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[7]</sup></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member] | 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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueNetAssetLiabilityAbstract', window );"><strong>Fair Value Measurements [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', 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">3,500<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsFairValueDisclosure', window );">Cash equivalents</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">146,281<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">86,262<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment in ProQR Therapeutics N.V.</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">406,435<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">117,080<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Corporate Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', 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>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities issued by U.S. Government Agencies [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', 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>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities issued by the U.S. Treasury [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">260,154<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">30,818<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', 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>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsFairValueDisclosure', window );">Cash equivalents</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment in ProQR Therapeutics N.V.</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,609,514<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">877,718<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Corporate Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,252,960<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">647,461<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities issued by U.S. Government Agencies [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">276,612<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">136,325<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities issued by the U.S. Treasury [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', 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>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">79,942<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">93,932<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CashAndCashEquivalentsFairValueDisclosure', window );">Cash equivalents</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EquitySecuritiesFvNi', window );">Investment in ProQR Therapeutics N.V.</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,349<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>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AssetsFairValueDisclosure', window );">Total</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,349<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>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Corporate Debt Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities issued by U.S. Government Agencies [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities issued by the U.S. Treasury [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByMeasurementFrequencyAxis=us-gaap_FairValueMeasurementsRecurringMember', window );">Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Available-for-sale securities</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
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<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 on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">Included in other current assets on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[3]</td>
<td style="vertical-align: top;" valign="top">$50.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[4]</td>
<td style="vertical-align: top;" valign="top">$11.9 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[5]</td>
<td style="vertical-align: top;" valign="top">Included in short-term investments on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[6]</td>
<td style="vertical-align: top;" valign="top">$14.2 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[7]</td>
<td style="vertical-align: top;" valign="top">$3.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.</td>
</tr>
</table></td></tr>
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<div style="display: none;">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Fair value portion of probable future economic benefits obtained or controlled by an entity as a result of past transactions or events.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=99377789&amp;loc=d3e19207-110258<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in debt and equity securities categorized neither as held-to-maturity nor trading.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Fair value portion of currency on hand as well as demand deposits with banks or financial institutions. Includes other kinds of accounts that have the general characteristics of demand deposits. Also includes short-term, highly liquid investments that are both readily convertible to known amounts of cash and so near their maturity that they present insignificant risk of changes in value because of changes in interest rates.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in equity security measured at fair value with change in fair value recognized in net income (FV-NI).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -URI http://asc.fasb.org/extlink&amp;oid=99377092&amp;loc=SL75136599-209740<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of transfers of assets measured on a recurring basis out of Level 1 of the fair value hierarchy into Level 2.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (bb)<br> -URI http://asc.fasb.org/extlink&amp;oid=99377789&amp;loc=d3e19207-110258<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FairValueAssetsLevel1ToLevel2TransfersAmount</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of transfers of assets measured on a recurring basis out of Level 2 of the fair value hierarchy into Level 1.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (bb)<br> -URI http://asc.fasb.org/extlink&amp;oid=99377789&amp;loc=d3e19207-110258<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FairValueAssetsLevel2ToLevel1TransfersAmount</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td><strong> Name:</strong></td>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6819491472">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Fair Value Measurements - Novartis Future Stock Purchase (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Jan. 31, 2017</div></th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember', window );">Novartis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_FutureStockPurchaseAbstract', window );"><strong>Novartis Future Stock Purchase [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AdditionalAmountOfCommonStockRequiredToBePurchased', window );">Additional amount of common stock required to be purchased</a></td>
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<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PotentialFuturePremium', window );">Fair value of potential future premium</a></td>
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<td class="nump">$ 5,000<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueByAssetClassAxis=ions_PotentialFuturePremiumMember', window );">Potential Future Premium [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationCalculationRollForward', window );"><strong>Unobservable Inputs (Level 3) [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisAssetValue', window );">Beginning balance of Level 3 instruments</a></td>
<td class="nump">$ 0<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisAssetTransfersIntoLevel3', window );">Value of the potential premium we will receive from Novartis at inception of the SPA (January 2017)</a></td>
<td class="nump">5,035<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisAssetGainLossIncludedInEarnings1', window );">Write-off of premium to other expenses</a></td>
<td class="num">(5,035)<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_FairValueMeasurementWithUnobservableInputsReconciliationRecurringBasisAssetValue', window );">Ending balance of Level 3 instruments</a></td>
<td class="nump">$ 0<span></span>
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<td class="text">&#160;<span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The additional amount of common stock the collaboration partner is required to purchase under a Stock Purchase Agreement (SPA) in conjunction with the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The fair value of the potential future premium the Company will receive if Novartis purchases its common stock under a Stock Purchase Agreement (SPA) entered into in January 2017.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of gain (loss) recognized in the income statement for financial instrument classified as an asset measured using unobservable inputs that reflect the entity's own assumption about the assumptions market participants would use in pricing.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=99377789&amp;loc=d3e19207-110258<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of transfer of financial instrument classified as an asset into level 3 of the fair value hierarchy.</p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Fair value of financial instrument classified as an asset measured using unobservable inputs that reflect the entity's own assumption about the assumptions market participants would use in pricing.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=99377789&amp;loc=d3e19207-110258<br></p></div>
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<body>
<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6803469200">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Organization and Significant Accounting Policies, Income Taxes (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateContinuingOperationsTaxRateReconciliationAbstract', window );"><strong>Income Taxes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance', window );">One-time non-cash tax benefit related to reversal of valuation allowance</a></td>
<td class="nump">$ 332,100<span></span>
</td>
<td class="num">$ (277,924)<span></span>
</td>
<td class="num">$ (86,296)<span></span>
</td>
<td class="nump">$ 46,402<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsValuationAllowance', window );">Valuation allowance</a></td>
<td class="nump">$ 234,245<span></span>
</td>
<td class="nump">$ 234,245<span></span>
</td>
<td class="nump">$ 468,702<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_DeferredTaxAssetsValuationAllowance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred tax assets for which it is more likely than not that a tax benefit will not be realized.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32537-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsValuationAllowance</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateContinuingOperationsTaxRateReconciliationAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateContinuingOperationsTaxRateReconciliationAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to increase (decrease) in the valuation allowance for deferred tax assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=84176650&amp;loc=d3e32123-109318<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6803625984">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Investments, Contract Maturity of Available-for-Sale Securities (Details)<br></strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th">
<div>Dec. 31, 2018 </div>
<div>Company</div>
</th></tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtMaturitiesAbstract', window );"><strong>Contract Maturity of Available-for-Sale Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage', window );">One year or less</a></td>
<td class="nump">77.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage', window );">After one year but within two years</a></td>
<td class="nump">20.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage', window );">After two years but within three and one 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="top.Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage', window );">Total</a></td>
<td class="nump">100.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage', window );">Percentage of available-for-sale securities with a maturity of less than two years</a></td>
<td class="nump">97.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumContractMaturityPeriodRange1', window );">Maximum contract maturity period, range 1</a></td>
<td class="text">1 year<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumContractMaturityPeriodRange2', window );">Maximum contract maturity period, range 2</a></td>
<td class="text">2 years<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumContractMaturityPeriodRange3', window );">Maximum contract maturity period, range 3</a></td>
<td class="text">3 years 6 months<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_invest_InvestmentsScheduleAbstract', window );"><strong>Ownership Interests in Private and Public Companies [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment', window );">Number of privately-held companies in which there is an equity ownership interest of less than 20%</a></td>
<td class="nump">4<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment', window );">Number of publicly-held companies in which there is an equity ownership interest of less than 20%</a></td>
<td class="nump">2<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_invest_InvestmentsScheduleAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">invest_InvestmentsScheduleAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>invest_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</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_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of available-for-sale debt securities that mature beyond one year but within two years of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AvailableForSaleSecuritiesDebtMaturitiesAfterOneThroughTwoYearsPercentage</td>
</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>num:percentItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>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_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of available-for-sale debt securities that mature beyond two years but within three and one-half years of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AvailableForSaleSecuritiesDebtMaturitiesAfterTwoThroughThreeAndOneHalfYearsPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The aggregate percentage of all available-for-sale debt securities, regardless of maturity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AvailableForSaleSecuritiesDebtMaturitiesTotalPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of available-for-sale debt securities that mature within one year of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AvailableForSaleSecuritiesDebtMaturitiesWithinOneYearPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>num:percentItemType</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>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_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of available-for-sale debt securities that mature within two years of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AvailableForSaleSecuritiesDebtMaturitiesWithinTwoYearsPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
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<td><strong> Data Type:</strong></td>
<td>num: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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum contract maturity period for the first range of available-for-sale securities, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumContractMaturityPeriodRange1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</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>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumContractMaturityPeriodRange2">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum contract maturity period for the second range of available-for-sale securities, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumContractMaturityPeriodRange2</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
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<td><strong> Balance Type:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum contract maturity period for the third range of available-for-sale securities, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumContractMaturityPeriodRange3</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of privately-held companies, in which the entity has an equity ownership interest of less than 20%, with which it conducts business. These are accounted for under the cost method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfPrivatelyHeldCompaniesInWhichEntityHasEquityInvestment</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</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>instant</td>
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</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of publicly-held companies, in which the entity has an equity ownership interest of less than 20%, with which it conducts business. These are accounted for at fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfPubliclyHeldCompaniesInWhichEntityHasEquityInvestment</td>
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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:integerItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleSecuritiesDebtMaturitiesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesDebtMaturitiesAbstract</td>
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<DOCUMENT>
<TYPE>XML
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<DESCRIPTION>IDEA: XBRL DOCUMENT
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<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6805227312">
<tr>
<th class="tl" colspan="2" rowspan="1"><div style="width: 200px;"><strong>Investments, Summary of Investments (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2"><div>Dec. 31, 2018</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesAmortizedCost', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 1,874,529<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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">556<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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(4,068)<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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,871,017<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>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentSecondaryCategorizationAxis=ions_SecuritiesWithMaturityOfOneYearOrLessMember', window );">Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">1,433,930<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 643,193<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">31<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">6<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(2,362)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(1,103)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,431,599<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">642,096<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentSecondaryCategorizationAxis=ions_SecuritiesWithMaturityOfMoreThanOneYearMember', window );">Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">439,387<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">268,401<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">388<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">8<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(1,706)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(1,969)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">438,069<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">266,440<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_DebtSecuritiesMember', window );">Available-for-sale Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">1,873,317<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">911,594<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">419<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">14<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(4,068)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(3,072)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">1,869,668<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">908,536<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_CorporateDebtSecuritiesMember', window );">Corporate Debt Securities [Member] | Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="nump">956,879<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">500,599<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">13<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">2<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(1,858)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(752)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">955,034<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">499,849<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_CorporateDebtSecuritiesMember', window );">Corporate Debt Securities [Member] | Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">299,018<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">148,663<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">194<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">8<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(1,286)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(1,059)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">297,926<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">147,612<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember', window );">Debt Securities issued by U.S. Government Agencies [Member] | Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">168,839<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">83,926<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">3<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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(104)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(212)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">168,738<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">83,714<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember', window );">Debt Securities issued by U.S. Government Agencies [Member] | Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">107,789<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">52,779<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">194<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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(109)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(168)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">107,874<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">52,611<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_USTreasurySecuritiesMember', window );">Debt Securities issued by the U.S. Treasury [Member] | Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">244,640<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">29,428<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">15<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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(77)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(17)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">244,578<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">29,411<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_USTreasurySecuritiesMember', window );">Debt Securities issued by the U.S. Treasury [Member] | Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">15,600<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1,409<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(24)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(2)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">15,576<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1,407<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember', window );">Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member] | Securities with Maturity of One Year or Less [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">63,572<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">29,240<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">4<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(323)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(122)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">63,249<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">29,122<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember', window );">Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member] | Securities with Maturity of More than One Year [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">16,980<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">65,550<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="num">(287)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(740)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">16,693<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 64,810<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_EquitySecuritiesMember', window );">Equity Securities [Member]</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract', window );"><strong>Summary of Investments [Abstract]</strong></a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleEquitySecuritiesAmortizedCostBasis', window );">Cost</a></td>
<td class="th" style="border-bottom: 0px;"><sup>[3]</sup></td>
<td class="nump">1,212<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>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleEquitySecuritiesAccumulatedGrossUnrealizedGainBeforeTax', window );">Gross unrealized gains</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">137<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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleEquitySecuritiesAccumulatedGrossUnrealizedLossBeforeTax', window );">Gross unrealized losses</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">0<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesEquitySecurities', window );">Estimated fair value</a></td>
<td class="th" style="border-bottom: 0px;"><sup></sup></td>
<td class="nump">$ 1,349<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>
</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">We hold our available-for-sale securities at amortized cost.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">Includes investments classified as cash equivalents on our consolidated balance sheet.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[3]</td>
<td style="vertical-align: top;" valign="top">We recognize our equity securities at 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 on our consolidated balance sheet.</td>
</tr>
</table></td></tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, before tax, of unrealized gain in accumulated other comprehensive income (AOCI) on investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=82897076&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, before tax, of unrealized loss in accumulated other comprehensive income (AOCI) on investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=82897076&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amortized cost of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=82897076&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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_AvailableForSaleEquitySecuritiesAccumulatedGrossUnrealizedGainBeforeTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before tax of unrealized gain in accumulated other comprehensive income (AOCI) on investments in equity securities classified as available-for-sale.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleEquitySecuritiesAccumulatedGrossUnrealizedGainBeforeTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleEquitySecuritiesAccumulatedGrossUnrealizedLossBeforeTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before tax of unrealized loss in accumulated other comprehensive income (AOCI) on investments in equity securities classified as available-for-sale.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleEquitySecuritiesAccumulatedGrossUnrealizedLossBeforeTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleEquitySecuritiesAmortizedCostBasis">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>This item represents the cost of equity securities, which are categorized neither as held-to-maturity nor trading, net of adjustments for other-than-temporary impairments recognized in earnings (less any cumulative-effect adjustments recognized, as defined), and fair value hedge accounting adjustments, if any.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleEquitySecuritiesAmortizedCostBasis</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleSecurities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in debt and equity securities categorized neither as held-to-maturity nor trading.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecurities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleSecuritiesAccumulatedGrossUnrealizedGainBeforeTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before tax of unrealized gain in accumulated other comprehensive income (AOCI) on investments in debt and equity securities classified as available-for-sale.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=82897076&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesAccumulatedGrossUnrealizedGainBeforeTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleSecuritiesAccumulatedGrossUnrealizedLossBeforeTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before tax of unrealized loss in accumulated other comprehensive income (AOCI) on investments in debt and equity securities classified as available-for-sale.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesAccumulatedGrossUnrealizedLossBeforeTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleSecuritiesAmortizedCost">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>This item represents the cost of debt and equity securities, which are categorized neither as held-to-maturity nor trading, net of adjustments including accretion, amortization, collection of cash, previous other-than-temporary impairments recognized in earnings (less any cumulative-effect adjustments recognized, as defined), and fair value hedge accounting adjustments, if any.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesAmortizedCost</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AvailableForSaleSecuritiesDebtSecurities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of investment in debt security measured at fair value with change in fair value recognized in other comprehensive income (available-for-sale).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109979856&amp;loc=d3e26610-111562<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 50<br> -Paragraph 2<br> -Subparagraph (aa)<br> -URI http://asc.fasb.org/extlink&amp;oid=82897076&amp;loc=d3e27161-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesDebtSecurities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleSecuritiesEquitySecurities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of equity securities categorized neither as held-to-maturity nor as trading.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesEquitySecurities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesFairValueToAmortizedCostBasisAbstract</td>
</tr>
<tr>
<td style="padding-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_InvestmentSecondaryCategorizationAxis=ions_SecuritiesWithMaturityOfOneYearOrLessMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentSecondaryCategorizationAxis=ions_SecuritiesWithMaturityOfOneYearOrLessMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentSecondaryCategorizationAxis=ions_SecuritiesWithMaturityOfMoreThanOneYearMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentSecondaryCategorizationAxis=ions_SecuritiesWithMaturityOfMoreThanOneYearMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentTypeAxis=us-gaap_DebtSecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentTypeAxis=us-gaap_DebtSecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentTypeAxis=us-gaap_CorporateDebtSecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentTypeAxis=us-gaap_CorporateDebtSecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentTypeAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentTypeAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentTypeAxis=us-gaap_USTreasurySecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentTypeAxis=us-gaap_USTreasurySecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentTypeAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentTypeAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_InvestmentTypeAxis=us-gaap_EquitySecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentTypeAxis=us-gaap_EquitySecuritiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
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<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6805253520">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Investments, Investments Temporarily Impaired (Details)<br> $ in Thousands</strong></div></th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($) </div>
<div>Investment</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableforsaleSecuritiesInUnrealizedLossPositionsQualitativeDisclosureNumberOfPositions1', window );">Number of investments | Investment</a></td>
<td class="nump">681<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThanTwelveMonthsFairValue', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 1,358,853<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">(2,159)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionTwelveMonthsOrLongerFairValue', window );">Estimated fair value, more than 12 months of temporary impairment</a></td>
<td class="nump">225,056<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss', window );">Unrealized losses, more than 12 months of temporary impairment</a></td>
<td class="num">(1,909)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionFairValue', window );">Estimated fair value, total temporary impairment</a></td>
<td class="nump">1,583,909<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLoss', window );">Unrealized losses, total temporary impairment</a></td>
<td class="num">$ (4,068)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_CorporateDebtSecuritiesMember', window );">Corporate Debt Securities [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableforsaleSecuritiesInUnrealizedLossPositionsQualitativeDisclosureNumberOfPositions1', window );">Number of investments | Investment</a></td>
<td class="nump">546<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThanTwelveMonthsFairValue', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 1,000,461<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">(1,936)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionTwelveMonthsOrLongerFairValue', window );">Estimated fair value, more than 12 months of temporary impairment</a></td>
<td class="nump">126,357<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss', window );">Unrealized losses, more than 12 months of temporary impairment</a></td>
<td class="num">(1,208)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionFairValue', window );">Estimated fair value, total temporary impairment</a></td>
<td class="nump">1,126,818<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLoss', window );">Unrealized losses, total temporary impairment</a></td>
<td class="num">$ (3,144)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember', window );">Debt Securities issued by U.S. Government Agencies [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableforsaleSecuritiesInUnrealizedLossPositionsQualitativeDisclosureNumberOfPositions1', window );">Number of investments | Investment</a></td>
<td class="nump">50<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThanTwelveMonthsFairValue', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 161,312<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">(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="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionTwelveMonthsOrLongerFairValue', window );">Estimated fair value, more than 12 months of temporary impairment</a></td>
<td class="nump">34,403<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss', window );">Unrealized losses, more than 12 months of temporary impairment</a></td>
<td class="num">(104)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionFairValue', window );">Estimated fair value, total temporary impairment</a></td>
<td class="nump">195,715<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLoss', window );">Unrealized losses, total temporary impairment</a></td>
<td class="num">$ (213)<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_USTreasurySecuritiesMember', window );">Debt Securities issued by the U.S. Treasury [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableforsaleSecuritiesInUnrealizedLossPositionsQualitativeDisclosureNumberOfPositions1', window );">Number of investments | Investment</a></td>
<td class="nump">36<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThanTwelveMonthsFairValue', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 183,212<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">(100)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionTwelveMonthsOrLongerFairValue', window );">Estimated fair value, more than 12 months of temporary impairment</a></td>
<td class="nump">1,413<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss', window );">Unrealized losses, more than 12 months of temporary impairment</a></td>
<td class="num">(1)<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionFairValue', window );">Estimated fair value, total temporary impairment</a></td>
<td class="nump">184,625<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLoss', window );">Unrealized losses, total temporary impairment</a></td>
<td class="num">$ (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="top.Show.showAR( this, 'defref_us-gaap_InvestmentTypeAxis=us-gaap_USStatesAndPoliticalSubdivisionsMember', window );">Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAbstract', window );"><strong>Temporarily Impaired Investments [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableforsaleSecuritiesInUnrealizedLossPositionsQualitativeDisclosureNumberOfPositions1', window );">Number of investments | Investment</a></td>
<td class="nump">49<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThanTwelveMonthsFairValue', window );">Estimated fair value, less than 12 months of temporary impairment</a></td>
<td class="nump">$ 13,868<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss', window );">Unrealized losses, less than 12 months of temporary impairment</a></td>
<td class="num">(14)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionTwelveMonthsOrLongerFairValue', window );">Estimated fair value, more than 12 months of temporary impairment</a></td>
<td class="nump">62,883<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss', window );">Unrealized losses, more than 12 months of temporary impairment</a></td>
<td class="num">(596)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionFairValue', window );">Estimated fair value, total temporary impairment</a></td>
<td class="nump">76,751<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLoss', window );">Unrealized losses, total temporary impairment</a></td>
<td class="num">$ (610)<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_AvailableForSaleSecuritiesContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of accumulated unrealized loss on investments in debt and equity securities classified as available-for-sale that have been in a continuous loss position for twelve months or longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPosition12MonthsOrLongerAccumulatedLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAbstract</td>
</tr>
<tr>
<td style="padding-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_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of accumulated unrealized loss on investments in debt and equity securities classified as available-for-sale in a continuous loss position.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=82897076&amp;loc=d3e27337-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionAccumulatedLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>This item represents the aggregate fair value of investments in debt and equity securities in an unrealized loss position which are categorized neither as held-to-maturity nor trading securities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of accumulated unrealized loss on investments in debt and equity securities classified as available-for-sale that have been in a continuous loss position for less than twelve months.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThan12MonthsAccumulatedLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThanTwelveMonthsFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>This item represents the aggregate fair value of investments in debt and equity securities categorized neither as held-to-maturity nor trading securities that have been in a continuous unrealized loss position for less than twelve months.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionLessThanTwelveMonthsFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionTwelveMonthsOrLongerFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>This item represents the aggregate fair value of investments in debt and equity securities categorized neither as held-to-maturity nor trading securities that have been in a continuous unrealized loss position for twelve months or longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableForSaleSecuritiesContinuousUnrealizedLossPositionTwelveMonthsOrLongerFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_AvailableforsaleSecuritiesInUnrealizedLossPositionsQualitativeDisclosureNumberOfPositions1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of investment positions in available-for-sale investments in a continuous unrealized loss position for which an other-than-temporary impairment (OTTI) has not been recognized in the income statement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 320<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -Subparagraph (b)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=82897076&amp;loc=d3e27290-111563<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AvailableforsaleSecuritiesInUnrealizedLossPositionsQualitativeDisclosureNumberOfPositions1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</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_InvestmentTypeAxis=us-gaap_CorporateDebtSecuritiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InvestmentTypeAxis=us-gaap_CorporateDebtSecuritiesMember</td>
</tr>
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<td style="white-space:nowrap;">us-gaap_InvestmentTypeAxis=us-gaap_USGovernmentAgenciesDebtSecuritiesMember</td>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6822741200">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Long-Term Obligations (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermDebtCurrentAndNoncurrentAbstract', window );"><strong>Long-Term Obligations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermDebtAndOtherObligations', window );">Total long-term obligations, including current portion</a></td>
<td class="nump">$ 646,720<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 607,477<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent', window );">Less: current portion</a></td>
<td class="num">(13,749)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(1,621)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermDebtAndOtherObligationsNoncurrent', window );">Total Long-Term Obligations</a></td>
<td class="nump">632,971<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">605,856<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermDebtCurrentAndNoncurrentAbstract', window );"><strong>Long-Term Obligations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermDebtAndOtherObligations', window );">Total long-term obligations, including current portion</a></td>
<td class="nump">568,215<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">533,111<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_LongTermMortgageDebtMember', window );">Long-term Mortgage Debt [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermDebtCurrentAndNoncurrentAbstract', window );"><strong>Long-Term Obligations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermDebtAndOtherObligations', window );">Total long-term obligations, including current portion</a></td>
<td class="nump">59,842<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">59,771<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_FixedRateNoteWithMorganStanleyMember', window );">Fixed Rate Note with Morgan Stanley [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermDebtCurrentAndNoncurrentAbstract', window );"><strong>Long-Term Obligations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
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<tr class="reu">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermDebtAndOtherObligations', window );">Total long-term obligations, including current portion</a></td>
<td class="nump">12,500<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1]</sup></td>
<td class="nump">12,500<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent', window );">Less: current portion</a></td>
<td class="num">(12,500)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_LeasesAndOtherObligationsMember', window );">Leases and Other Obligations [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongtermDebtCurrentAndNoncurrentAbstract', window );"><strong>Long-Term Obligations [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
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<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermDebtAndOtherObligations', window );">Total long-term obligations, including current portion</a></td>
<td class="nump">$ 6,163<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 2,095<span></span>
</td>
</tr>
<tr><td colspan="4"></td></tr>
<tr><td colspan="4"><table class="outerFootnotes" width="100%"><tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[1]</td>
<td style="vertical-align: top;" valign="top">Our $12.5 million fixed rate note with Morgan Stanley is included in our current portion of long-term obligations on our consolidated balance sheet at December 31, 2018.</td>
</tr></table></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Including the current and noncurrent portions, aggregate carrying value as of the balance sheet date of long-term debt, capital lease and other obligations (with maturities initially due after one year or beyond the operating cycle if longer).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term debt, capital lease and other obligations due after one year or beyond the normal operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term debt and capital leases due within one year or the normal operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.20)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_LeasesAndOtherObligationsMember</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>
</table>
</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>85
<FILENAME>R53.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6819475376">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Convertible Notes (Details)<br> $ / shares in Units, $ in Thousands</strong></div></th>
<th class="th" colspan="2">1 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Nov. 30, 2014 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($) </div>
<div>shares </div>
<div>$ / shares</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
</th>
<th class="th"><div>Mar. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="num">$ (3,983)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AmortizationOfFinancingCostsAndDiscounts', window );">Amortization of debt discount and debt issuance costs</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">35,200<span></span>
</td>
<td class="nump">32,500<span></span>
</td>
<td class="nump">$ 25,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">Long-term debt</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 568,215<span></span>
</td>
<td class="nump">$ 533,111<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentMaturityDate', window );">Maturity date</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">Nov. 30,  2021<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentConvertibleConversionPrice1', window );">Conversion price per share (in dollars per share) | $ / shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 66.81<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments', window );">Total shares of common stock subject to conversion (in shares) | shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,300,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange', window );">Percentage of principal amount used a 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>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentCarryingAmount', window );">Principal amount of convertible notes outstanding</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 685,450<span></span>
</td>
<td class="nump">$ 685,450<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentUnamortizedDiscountPremiumNet', window );">Unamortized portion of debt discount</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">110,817<span></span>
</td>
<td class="nump">144,112<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleDebtNoncurrent', window );">Long-term debt</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">568,215<span></span>
</td>
<td class="nump">533,111<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent', window );">Carrying value of equity component</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">219,011<span></span>
</td>
<td class="nump">219,011<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member] | Level 2 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermDebtFairValue', window );">Fair value of outstanding notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 724,966<span></span>
</td>
<td class="nump">$ 727,420<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentIssuedInNovember2014Member', window );">1 Percent Convertible Senior Notes Issued in November 2014 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentFaceAmount', window );">Face amount of offering</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 500,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromConvertibleDebt', window );">Proceeds from issuance of 1 percent convertible senior notes, net of issuance costs</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">487,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentIssuanceDate1', window );">Issue date</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">Nov. 30,  2014<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage', window );">Effective interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">7.80%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentConvertibleRemainingDiscountAmortizationPeriod1', window );">Amortization period of debt discount</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">7 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentIssuedInNovember2014Member', window );">1 Percent Convertible Senior Notes Issued in November 2014 [Member] | Borrowing Rate [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentMeasurementInput', window );">Debt measurement input rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.074<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentIssuedInDecember2016Member', window );">1 Percent Convertible Senior Notes Issued in December 2016 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentFaceAmount', window );">Face amount of offering</a></td>
<td class="nump">$ 185,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 185,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentIssuanceDate1', window );">Issue date</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">Dec. 31,  2016<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage', window );">Effective interest rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">7.20%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentConvertibleRemainingDiscountAmortizationPeriod1', window );">Amortization period of debt discount</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentIssuedInDecember2016Member', window );">1 Percent Convertible Senior Notes Issued in December 2016 [Member] | Borrowing Rate [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentMeasurementInput', window );">Debt measurement input rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.068<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember', window );">2 3/4 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract', window );"><strong>Convertible Notes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentRepurchasedFaceAmount', window );">Principal amount repurchased</a></td>
<td class="nump">61,100<span></span>
</td>
<td class="nump">140,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 61,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RepaymentsOfConvertibleDebt', window );">Repurchase of convertible senior notes</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">441,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_GainsLossesOnExtinguishmentOfDebt', window );">Loss on early retirement of debt</a></td>
<td class="nump">$ 3,983<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="nump">2.75%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentCarryingAmount', window );">Principal amount of convertible notes outstanding</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 61,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of the principal amount of the notes to be purchased, plus accrued and unpaid interest, upon the occurrence of certain fundamental changes, as set forth in the indenture governing the convertible notes.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DebtInstrumentConvertiblePercentageOfPrincipalAmountUsedAPurchasePriceUponOccurrenceOfFundamentalChange</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<tr>
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<td>num: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_AmortizationOfFinancingCostsAndDiscounts">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of amortization expense attributable to debt discount (premium) and debt issuance costs.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&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 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&amp;loc=d3e28555-108399<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AmortizationOfFinancingCostsAndDiscounts</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConvertibleDebtNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Carrying amount of long-term convertible debt as of the balance sheet date, net of the amount due in the next twelve months or greater than the normal operating cycle, if longer. The debt is convertible into another form of financial instrument, typically the entity's common stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConvertibleDebtNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConvertibleLongtermNotesPayableCurrentAndNoncurrentAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentCarryingAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, before unamortized (discount) premium and debt issuance costs, of long-term debt. Includes, but is not limited to, notes payable, bonds payable, commercial loans, mortgage loans, convertible debt, subordinated debt and other types of debt.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (b)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109500613&amp;loc=SL6031897-161870<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&amp;loc=d3e572229-122910<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=6876686&amp;loc=d3e534808-122878<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentCarryingAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The carrying amount of the equity component of convertible debt which may be settled in cash upon conversion.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109500613&amp;loc=SL6031897-161870<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentConvertibleCarryingAmountOfTheEquityComponent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentConvertibleConversionPrice1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The price per share of the conversion feature embedded in the debt instrument.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 5<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109500613&amp;loc=SL6031898-161870<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><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>num: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_DebtInstrumentConvertibleNumberOfEquityInstruments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of equity instruments that the holder of the debt instrument would receive if the debt was converted to equity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>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 3<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21475-112644<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 50<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21521-112644<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21506-112644<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)(5))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentConvertibleNumberOfEquityInstruments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentConvertibleRemainingDiscountAmortizationPeriod1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Remaining amortization period for discount on the liability component of convertible debt which may be settled in cash upon conversion, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 5<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109500613&amp;loc=SL6031898-161870<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentConvertibleRemainingDiscountAmortizationPeriod1</td>
</tr>
<tr>
<td style="padding-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_DebtInstrumentFaceAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Face (par) amount of debt instrument at time of issuance.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&amp;loc=d3e28551-108399<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 55<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=114775985&amp;loc=d3e28878-108400<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentFaceAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateEffectivePercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Effective interest rate for the funds borrowed under the debt agreement considering interest compounding and original issue discount or premium.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 20<br> -Section 50<br> -Paragraph 6<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109500613&amp;loc=SL6036836-161870<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&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 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateEffectivePercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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_DebtInstrumentIssuanceDate1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Date the debt instrument was issued, in CCYY-MM-DD format.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://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))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentIssuanceDate1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:dateItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentMaturityDate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Date when the debt instrument is scheduled to be fully repaid, in CCYY-MM-DD format.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&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 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (bbb)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=99377789&amp;loc=d3e19207-110258<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentMaturityDate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:dateItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentMeasurementInput">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Value of input used to measure debt instrument, including, but not limited to, convertible and non-convertible debt.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (bbb)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=99377789&amp;loc=d3e19207-110258<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentMeasurementInput</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:decimalItemType</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_DebtInstrumentRepurchasedFaceAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Face (par) amount of the original debt instrument that was repurchased.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentRepurchasedFaceAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_DebtInstrumentUnamortizedDiscountPremiumNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after accumulated amortization, of debt discount (premium).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&amp;loc=d3e28555-108399<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&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 45<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&amp;loc=d3e28567-108399<br><br>Reference 4: 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 1A<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&amp;loc=d3e28541-108399<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 55<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=114775985&amp;loc=d3e28878-108400<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentUnamortizedDiscountPremiumNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_GainsLossesOnExtinguishmentOfDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Difference between the fair value of payments made and the carrying amount of debt which is extinguished prior to maturity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 4<br> -URI http://asc.fasb.org/extlink&amp;oid=114001942&amp;loc=d3e12355-112629<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 470<br> -SubTopic 50<br> -Section 40<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=114001942&amp;loc=d3e12317-112629<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_GainsLossesOnExtinguishmentOfDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LongTermDebtFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The fair value amount of long-term debt whether such amount is presented as a separate caption or as a parenthetical disclosure. Additionally, this element may be used in connection with the fair value disclosures required in the footnote disclosures to the financial statements. The element may be used in both the balance sheet and disclosure in the same submission.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LongTermDebtFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_ProceedsFromConvertibleDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from the issuance of a long-term debt instrument which can be exchanged for a specified amount of another security, typically the entity's common stock, at the option of the issuer or the holder.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromConvertibleDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RepaymentsOfConvertibleDebt">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow from the repayment of a long-term debt instrument which can be exchanged for a specified amount of another security, typically the entity's common stock, at the option of the issuer or the holder.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3291-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RepaymentsOfConvertibleDebt</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_FairValueByFairValueHierarchyLevelAxis=us-gaap_FairValueInputsLevel2Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_FairValueByFairValueHierarchyLevelAxis=us-gaap_FairValueInputsLevel2Member</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_ConvertibleSeniorNotes1PercentIssuedInNovember2014Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentIssuedInNovember2014Member</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_MeasurementInputTypeAxis=us-gaap_MeasurementInputDiscountRateMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MeasurementInputTypeAxis=us-gaap_MeasurementInputDiscountRateMember</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_ConvertibleSeniorNotes1PercentIssuedInDecember2016Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentIssuedInDecember2016Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember</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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<DESCRIPTION>IDEA: XBRL DOCUMENT
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<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6805808816">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Financing Arrangements (Details)<br> $ in Millions</strong></div></th>
<th class="th" colspan="1">12 Months Ended</th>
</tr>
<tr><th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th></tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_FixedRateNoteWithMorganStanleyMember', window );">Fixed Rate Note with Morgan Stanley [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LineOfCreditFacilityAbstract', window );"><strong>Financing Arrangements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LineOfCredit', window );">Outstanding borrowings</a></td>
<td class="nump">$ 12.5<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="nump">2.31%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentMaturityDate', window );">Maturity date</a></td>
<td class="text">Sep. 30,  2019<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LineOfCreditFacilityAxis=ions_MorganStanleyPrivateBankNationalAssociationMember', window );">Morgan Stanley [Member] | Revolving Line of Credit [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LineOfCreditFacilityAbstract', window );"><strong>Financing Arrangements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentTerm', window );">Term of agreement</a></td>
<td class="text">5 years<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LineOfCreditFacilityMaximumBorrowingCapacity', window );">Maximum borrowing capacity</a></td>
<td class="nump">$ 30.0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LineOfCreditFacilityUnusedCapacityCommitmentFeePercentage', window );">Commitment fee percentage on unused capacity</a></td>
<td class="nump">0.25%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LineOfCreditFacilityAxis=ions_MorganStanleyPrivateBankNationalAssociationMember', window );">Morgan Stanley [Member] | Revolving Line of Credit [Member] | LIBOR [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LineOfCreditFacilityAbstract', window );"><strong>Financing Arrangements [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_TermOfVariableRate', window );">Term of variable rate</a></td>
<td class="text">1 month<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentBasisSpreadOnVariableRate1', window );">Basis spread on variable rate</a></td>
<td class="nump">1.25%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentDescriptionOfVariableRateBasis', window );">Term of fixed rate elected</a></td>
<td class="text">one, two, three, four, six, or twelve months<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_TermOfVariableRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Term of the variable rate.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_TermOfVariableRate</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>
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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_DebtInstrumentBasisSpreadOnVariableRate1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage points added to the reference rate to compute the variable rate on the debt instrument.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentBasisSpreadOnVariableRate1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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_DebtInstrumentDescriptionOfVariableRateBasis">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The reference rate for the variable rate of the debt instrument, such as LIBOR or the US Treasury rate and the maturity of the reference rate used, such as three months or six months LIBOR.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentDescriptionOfVariableRateBasis</td>
</tr>
<tr>
<td style="padding-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_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentMaturityDate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Date when the debt instrument is scheduled to be fully repaid, in CCYY-MM-DD format.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&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 820<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (bbb)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=99377789&amp;loc=d3e19207-110258<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentMaturityDate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:dateItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentTerm">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time between issuance and maturity of debt instrument, in PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentTerm</td>
</tr>
<tr>
<td style="padding-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_LineOfCredit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The carrying value as of the balance sheet date of the current and noncurrent portions of long-term obligations drawn from a line of credit, which is a bank's commitment to make loans up to a specific amount. Examples of items that might be included in the application of this element may consist of letters of credit, standby letters of credit, and revolving credit arrangements, under which borrowings can be made up to a maximum amount as of any point in time conditional on satisfaction of specified terms before, as of and after the date of drawdowns on the line. Includes short-term obligations that would normally be classified as current liabilities but for which (a) postbalance sheet date issuance of a long term obligation to refinance the short term obligation on a long term basis, or (b) the enterprise has entered into a financing agreement that clearly permits the enterprise to refinance the short-term obligation on a long term basis and the following conditions are met (1) the agreement does not expire within 1 year and is not cancelable by the lender except for violation of an objectively determinable provision, (2) no violation exists at the BS date, and (3) the lender has entered into the financing agreement is expected to be financially capable of honoring the agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=6876686&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(16))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&amp;loc=d3e572229-122910<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LineOfCredit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_LineOfCreditFacilityAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LineOfCreditFacilityAbstract</td>
</tr>
<tr>
<td style="padding-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_LineOfCreditFacilityMaximumBorrowingCapacity">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Maximum borrowing capacity under the credit facility without consideration of any current restrictions on the amount that could be borrowed or the amounts currently outstanding under the facility.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.19(b),22(b))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LineOfCreditFacilityMaximumBorrowingCapacity</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<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_LineOfCreditFacilityUnusedCapacityCommitmentFeePercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The fee, expressed as a percentage of the line of credit facility, for available but unused credit capacity under the credit facility.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LineOfCreditFacilityUnusedCapacityCommitmentFeePercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
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<td><strong> Data Type:</strong></td>
<td>num: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_DebtInstrumentAxis=ions_FixedRateNoteWithMorganStanleyMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_FixedRateNoteWithMorganStanleyMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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<td><strong> Balance Type:</strong></td>
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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_us-gaap_LineOfCreditFacilityAxis=ions_MorganStanleyPrivateBankNationalAssociationMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LineOfCreditFacilityAxis=ions_MorganStanleyPrivateBankNationalAssociationMember</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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<td><strong> Balance Type:</strong></td>
<td></td>
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<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_us-gaap_CreditFacilityAxis=us-gaap_RevolvingCreditFacilityMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CreditFacilityAxis=us-gaap_RevolvingCreditFacilityMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_VariableRateAxis=us-gaap_LondonInterbankOfferedRateLIBORMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_VariableRateAxis=us-gaap_LondonInterbankOfferedRateLIBORMember</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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<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6823593168">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Research and Development and Manufacturing Facilities (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Jul. 31, 2017</div></th>
<th class="th"><div>Sep. 30, 2017</div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipmentAbstract', window );"><strong>Research and Development and Manufacturing Facilities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_GainLossOnExtinguishmentOfFinancingLiability', window );">Loss on extinguishment of financing liability for leased facility</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="num">$ (7,689)<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_PrimaryResearchAndDevelopmentFacilityMember', window );">Primary R&amp;D Facility [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipmentAbstract', window );"><strong>Research and Development and Manufacturing Facilities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquireBuildings', window );">Payment to acquire building</a></td>
<td class="nump">$ 79,400<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_GainLossOnExtinguishmentOfFinancingLiability', window );">Loss on extinguishment of financing liability for leased facility</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (7,689)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromLoanOriginations1', window );">Proceeds from mortgage loan</a></td>
<td class="nump">$ 51,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="nump">3.88%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan', window );">Period to make interest only payments on mortgage loan</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_ManufacturingFacilityMember', window );">Manufacturing Facility [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipmentAbstract', window );"><strong>Research and Development and Manufacturing Facilities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PaymentsToAcquireBuildings', window );">Payment to acquire building</a></td>
<td class="nump">$ 14,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromLoanOriginations1', window );">Proceeds from mortgage loan</a></td>
<td class="nump">$ 9,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate</a></td>
<td class="nump">4.20%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan', window );">Period to make interest only payments on mortgage loan</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_GainLossOnExtinguishmentOfFinancingLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Difference between the purchase price of the facility and the carrying value of our financing liability at the time of the purchase.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_GainLossOnExtinguishmentOfFinancingLiability</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_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time to make only payments of interest on the mortgage loan, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PeriodToMakeInterestOnlyPaymentsOnMortgageLoan</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentInterestRateStatedPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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_PaymentsToAcquireBuildings">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash outflow for acquisition of buildings (properties) whether for investment or use.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 13<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3213-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToAcquireBuildings</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PaymentsToAcquirePropertyPlantAndEquipmentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PaymentsToAcquirePropertyPlantAndEquipmentAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</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_ProceedsFromLoanOriginations1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cash inflow associated with loan origination (the process when securing a mortgage for a piece of real property) or lease origination.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3179-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromLoanOriginations1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_PropertyPlantAndEquipmentByTypeAxis=ions_PrimaryResearchAndDevelopmentFacilityMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=ions_PrimaryResearchAndDevelopmentFacilityMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_ManufacturingFacilityMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PropertyPlantAndEquipmentByTypeAxis=us-gaap_ManufacturingFacilityMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6804774752">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Maturity Schedules (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract', window );"><strong>Annual Debt and Other Obligation Maturities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent', window );">Less: current portion</a></td>
<td class="num">$ (13,749)<span></span>
</td>
<td class="num">$ (1,621)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermDebtAndOtherObligationsNoncurrent', window );">Total</a></td>
<td class="nump">632,971<span></span>
</td>
<td class="nump">$ 605,856<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember', window );">Long-Term Obligations, Excluding Financing Liability for Leased Facility [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract', window );"><strong>Annual Debt and Other Obligation Maturities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueInNextTwelveMonths', window );">2019</a></td>
<td class="nump">22,067<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueInSecondYear', window );">2020</a></td>
<td class="nump">9,330<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueInThirdYear', window );">2021</a></td>
<td class="nump">694,774<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueInFourthYear', window );">2022</a></td>
<td class="nump">2,809<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueInFifthYear', window );">2023</a></td>
<td class="nump">3,494<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligationDueAfterFifthYear', window );">Thereafter</a></td>
<td class="nump">68,108<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractualObligation', window );">Subtotal</a></td>
<td class="nump">800,582<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent', window );">Less: current portion</a></td>
<td class="num">(12,890)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_InterestPayableCurrentAndNoncurrent', window );">Less: fixed and determinable interest</a></td>
<td class="num">(41,837)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentUnamortizedDiscount', window );">Less: unamortized portion of debt discount</a></td>
<td class="num">(111,426)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredRentCredit', window );">Plus: Deferred rent</a></td>
<td class="nump">4,960<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LongTermDebtAndOtherObligationsNoncurrent', window );">Total</a></td>
<td class="nump">$ 639,389<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_LongTermDebtAndOtherObligationsNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term debt, capital lease and other obligations due after one year or beyond the normal operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ 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_LongTermDebtAndOtherObligationsNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation, including but not limited to, long-term debt, capital lease obligations, operating lease obligations, purchase obligations, and other commitments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligation</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation due after the fifth fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueAfterFifthYear</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueInFifthYear">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation due in the fifth fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueInFifthYear</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueInFourthYear">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation due in the fourth fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueInFourthYear</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueInNextTwelveMonths">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation due in the next fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueInNextTwelveMonths</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueInSecondYear">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation due in the second fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueInSecondYear</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractualObligationDueInThirdYear">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of contractual obligation due in the third fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractualObligationDueInThirdYear</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentUnamortizedDiscount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after accumulated amortization, of debt discount.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 835<br> -SubTopic 30<br> -Section 45<br> -Paragraph 1A<br> -URI http://asc.fasb.org/extlink&amp;oid=114775744&amp;loc=d3e28541-108399<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 55<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=114775985&amp;loc=d3e28878-108400<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentUnamortizedDiscount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_DeferredRentCredit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cumulative difference between the rental payments required by a lease agreement and the rental income or expense recognized on a straight-line basis, or other systematic and rational basis more representative of the time pattern in which use or benefit is granted or derived from the leased property, expected to be recognized in income or expense over the term of the leased property by the lessor or lessee, respectively.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 20<br> -Section 25<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=77902458&amp;loc=d3e39896-112707<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredRentCredit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_InterestPayableCurrentAndNoncurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of interest payable on debt, including, but not limited to, trade payables.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03.15(5))<br> -URI http://asc.fasb.org/extlink&amp;oid=6876686&amp;loc=d3e534808-122878<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-03.15(a))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&amp;loc=d3e572229-122910<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_InterestPayableCurrentAndNoncurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of long-term debt and capital leases due within one year or the normal operating cycle, if longer.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.20)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LongTermDebtAndCapitalLeaseObligationsCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MaturitiesOfLongtermDebtAndCapitalLeaseObligationsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></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>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DebtInstrumentAxis=ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DebtInstrumentAxis=ions_LongTermObligationsExcludingFinancingLiabilityForLeasedFacilityMember</td>
</tr>
<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>
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<tr>
<td><strong> Period Type:</strong></td>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Long-Term Obligations and Commitments, Operating Leases (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
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<tr>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($) </div>
<div>Option</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
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<th class="th">
<div>Aug. 15, 2018 </div>
<div>USD ($)</div>
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<th class="th"><div>Apr. 05, 2018</div></th>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LeaseArrangementTypeAxis=ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember', window );">Office and Laboratory Space Adjacent to Manufacturing Facility [Member]</a></td>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LeasesOperatingAbstract', window );"><strong>Operating Leases [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease', window );">Number of options to extend lease | Option</a></td>
<td class="nump">2<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseRenewalTerm', window );">Term of lease extension</a></td>
<td class="text">5 years<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract', window );"><strong>Annual Future Minimum Payments Under Operating Leases [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent', window );">2019</a></td>
<td class="nump">$ 3,129<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeasesFutureMinimumPaymentsDueInTwoYears', window );">2020</a></td>
<td class="nump">3,008<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears', window );">2021</a></td>
<td class="nump">2,725<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears', window );">2022</a></td>
<td class="nump">2,539<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFiveYears', window );">2023</a></td>
<td class="nump">2,505<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter', window );">Thereafter</a></td>
<td class="nump">11,862<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeasesFutureMinimumPaymentsDue', window );">Total minimum payments</a></td>
<td class="nump">25,768<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLeasesRentExpenseMinimumRentals', window );">Rent expense</a></td>
<td class="nump">2,600<span></span>
</td>
<td class="nump">$ 1,700<span></span>
</td>
<td class="nump">$ 2,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredRentCredit', window );">Deferred rent</a></td>
<td class="nump">$ 5,000<span></span>
</td>
<td class="nump">$ 100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LeaseArrangementTypeAxis=ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember', window );">Office Space Subleased to Akcea [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LeasesOperatingAbstract', window );"><strong>Operating Leases [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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease', window );">Number of options to extend lease | Option</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseRenewalTerm', window );">Term of lease extension</a></td>
<td class="text">5 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Office Space for Corporate Headquarters [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LeasesOperatingAbstract', window );"><strong>Operating Leases [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseRenewalTerm', window );">Term of lease extension</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">5 years<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LesseeOperatingLeaseTermOfContract', window );">Term of lease</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">123 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="top.Show.showAR( this, 'defref_ions_LesseeOperatingLeasePeriodOfFreeRent', window );">Period of free rent under lease</a></td>
<td class="text">3 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeOperatingLeaseAllowanceForTenantImprovements', window );">Tenant improvement allowance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 3,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation', window );">Initial amount of letter of credit</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,400<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="top.Show.showAR( this, 'defref_ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate', window );">Letter of credit on third anniversary of rent commencement date</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate', window );">Letter of credit on fifth anniversary of rent commencement date</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,200<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_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of options to extend the lease under the lessee's operating leasing arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LesseeLeasingArrangementsOperatingLeasesNumberOfOptionsToExtendLease</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LesseeOperatingLeaseAllowanceForTenantImprovements">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Allowance for tenant improvements to the office space included in the lessee's operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LesseeOperatingLeaseAllowanceForTenantImprovements</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Initial letter of credit provided to lessor to secure lease obligation under lessee's operating lease.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LesseeOperatingLeaseInitialLetterOfCreditToSecureLeaseObligation</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_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Letter of credit provided to lessor to secure lease obligation under lessee's operating lease on the fifth anniversary of the rent commencement date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnFifthAnniversaryOfRentCommencementDate</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_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Letter of credit provided to lessor to secure lease obligation under lessee's operating lease on the third anniversary of the rent commencement date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LesseeOperatingLeaseLetterOfCreditToSecureLeaseObligationOnThirdAnniversaryOfRentCommencementDate</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_LesseeOperatingLeasePeriodOfFreeRent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time in which the rent is free under operating lease, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LesseeOperatingLeasePeriodOfFreeRent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredRentCredit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cumulative difference between the rental payments required by a lease agreement and the rental income or expense recognized on a straight-line basis, or other systematic and rational basis more representative of the time pattern in which use or benefit is granted or derived from the leased property, expected to be recognized in income or expense over the term of the leased property by the lessor or lessee, respectively.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 20<br> -Section 25<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=77902458&amp;loc=d3e39896-112707<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredRentCredit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<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_LeasesOperatingAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LeasesOperatingAbstract</td>
</tr>
<tr>
<td style="padding-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>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseRenewalTerm">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Term of lessee's operating lease renewal, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=77888426&amp;loc=SL77918673-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseRenewalTerm</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LesseeOperatingLeaseTermOfContract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Term of lessee's operating lease, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 842<br> -SubTopic 20<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=77888426&amp;loc=SL77918673-209980<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LesseeOperatingLeaseTermOfContract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLeasesFutureMinimumPaymentsDue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of required minimum rental payments for leases having an initial or remaining non-cancelable letter-terms in excess of one year.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 10<br> -Section 55<br> -Paragraph 40<br> -Subparagraph (Note 3)<br> -URI http://asc.fasb.org/extlink&amp;oid=82846649&amp;loc=d3e38371-112697<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 20<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=77902758&amp;loc=d3e41502-112717<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeasesFutureMinimumPaymentsDue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_OperatingLeasesFutureMinimumPaymentsDueCurrent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of required minimum rental payments for operating leases having an initial or remaining non-cancelable lease term in excess of one year due in the next fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 20<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=77902758&amp;loc=d3e41502-112717<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 10<br> -Section 55<br> -Paragraph 40<br> -Subparagraph (Note 3)<br> -URI http://asc.fasb.org/extlink&amp;oid=82846649&amp;loc=d3e38371-112697<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeasesFutureMinimumPaymentsDueCurrent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_OperatingLeasesFutureMinimumPaymentsDueInFiveYears">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of required minimum rental payments for operating leases having an initial or remaining non-cancelable lease term in excess of one year due in the fifth fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 20<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=77902758&amp;loc=d3e41502-112717<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 10<br> -Section 55<br> -Paragraph 40<br> -Subparagraph (Note 3)<br> -URI http://asc.fasb.org/extlink&amp;oid=82846649&amp;loc=d3e38371-112697<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFiveYears</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_OperatingLeasesFutureMinimumPaymentsDueInFourYears">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of required minimum rental payments for operating leases having an initial or remaining non-cancelable lease term in excess of one year due in the fourth fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 10<br> -Section 55<br> -Paragraph 40<br> -Subparagraph (Note 3)<br> -URI http://asc.fasb.org/extlink&amp;oid=82846649&amp;loc=d3e38371-112697<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 20<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=77902758&amp;loc=d3e41502-112717<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeasesFutureMinimumPaymentsDueInFourYears</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_OperatingLeasesFutureMinimumPaymentsDueInThreeYears">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of required minimum rental payments for operating leases having an initial or remaining non-cancelable lease term in excess of one year due in the third fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 10<br> -Section 55<br> -Paragraph 40<br> -Subparagraph (Note 3)<br> -URI http://asc.fasb.org/extlink&amp;oid=82846649&amp;loc=d3e38371-112697<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 20<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=77902758&amp;loc=d3e41502-112717<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeasesFutureMinimumPaymentsDueInThreeYears</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_OperatingLeasesFutureMinimumPaymentsDueInTwoYears">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of required minimum rental payments for operating leases having an initial or remaining non-cancelable lease term in excess of one year due in the second fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 10<br> -Section 55<br> -Paragraph 40<br> -Subparagraph (Note 3)<br> -URI http://asc.fasb.org/extlink&amp;oid=82846649&amp;loc=d3e38371-112697<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 20<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=77902758&amp;loc=d3e41502-112717<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeasesFutureMinimumPaymentsDueInTwoYears</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_OperatingLeasesFutureMinimumPaymentsDueThereafter">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of required minimum rental payments for operating leases having an initial or remaining non-cancelable lease term in excess of one year due after the fifth fiscal year following the latest fiscal year. Excludes interim and annual periods when interim periods are reported on a rolling approach, from latest balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 20<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=77902758&amp;loc=d3e41502-112717<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 10<br> -Section 55<br> -Paragraph 40<br> -Subparagraph (Note 3)<br> -URI http://asc.fasb.org/extlink&amp;oid=82846649&amp;loc=d3e38371-112697<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeasesFutureMinimumPaymentsDueThereafter</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_OperatingLeasesFutureMinimumPaymentsReceivableAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeasesFutureMinimumPaymentsReceivableAbstract</td>
</tr>
<tr>
<td style="padding-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_OperatingLeasesRentExpenseMinimumRentals">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>This element represents the payments that the lessee is obligated to make or can be required to make in connection with a property under the terms of an agreement classified as an operating lease, excluding contingent rentals and a guarantee by the lessee of the lessor's debt and the lessee's obligation to pay (apart from the rental payments) executory costs such as insurance, maintenance, and taxes.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 20<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=77902758&amp;loc=d3e41499-112717<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 10<br> -Section 25<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=77910348&amp;loc=d3e34039-112682<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 840<br> -SubTopic 10<br> -Section 55<br> -Paragraph 40<br> -Subparagraph (Note 3)<br> -URI http://asc.fasb.org/extlink&amp;oid=82846649&amp;loc=d3e38371-112697<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLeasesRentExpenseMinimumRentals</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LeaseArrangementTypeAxis=ions_OfficeAndLaboratorySpaceAdjacentToManufacturingFacilityMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LeaseArrangementTypeAxis=ions_OfficeSpaceSubleasedToAkceaTherapeuticsIncMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember</td>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6803101200">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Preferred and Common Stock (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockNumberOfSharesParValueAndOtherDisclosuresAbstract', window );"><strong>Common Stock [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesAuthorized', window );">Common stock, shares authorized to issue (in shares)</a></td>
<td class="nump">300,000,000<span></span>
</td>
<td class="nump">300,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesIssued', window );">Common stock, shares issued (in shares)</a></td>
<td class="nump">137,928,828<span></span>
</td>
<td class="nump">124,976,373<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesOutstanding', window );">Common stock, shares outstanding (in shares)</a></td>
<td class="nump">137,928,828<span></span>
</td>
<td class="nump">124,976,373<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions', window );">Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases</a></td>
<td class="nump">$ 27,900<span></span>
</td>
<td class="nump">$ 22,931<span></span>
</td>
<td class="nump">$ 13,417<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementClassOfStockAxis=us-gaap_PreferredStockMember', window );">Preferred Stock [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockNumberOfSharesParValueAndOtherDisclosuresAbstract', window );"><strong>Preferred Stock [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockSharesAuthorized', window );">Preferred stock, shares authorized (in shares)</a></td>
<td class="nump">15,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockSharesOutstanding', window );">Preferred stock, shares outstanding (in shares)</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementClassOfStockAxis=us-gaap_SeriesCPreferredStockMember', window );">Series C Junior Participating Preferred Stock [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockNumberOfSharesParValueAndOtherDisclosuresAbstract', window );"><strong>Preferred Stock [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockSharesIssued', window );">Preferred stock, shares issued (in shares)</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockSharesOutstanding', window );">Preferred stock, shares outstanding (in shares)</a></td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementClassOfStockAxis=us-gaap_CommonStockMember', window );">Common Stock [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockNumberOfSharesParValueAndOtherDisclosuresAbstract', window );"><strong>Common Stock [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesAuthorized', window );">Common stock, shares authorized to issue (in shares)</a></td>
<td class="nump">300,000,000<span></span>
</td>
<td class="nump">300,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesIssued', window );">Common stock, shares issued (in shares)</a></td>
<td class="nump">137,928,828<span></span>
</td>
<td class="nump">124,976,373<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockSharesOutstanding', window );">Common stock, shares outstanding (in shares)</a></td>
<td class="nump">137,928,828<span></span>
</td>
<td class="nump">124,976,373<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CommonStockCapitalSharesReservedForFutureIssuance', window );">Common shares reserved for future issuance (in shares)</a></td>
<td class="nump">14,839,373<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensationGross', window );">Number of shares issued for stock option exercises, vesting of restricted stock units, and ESPP purchases (in shares)</a></td>
<td class="nump">1,451,000<span></span>
</td>
<td class="nump">1,709,000<span></span>
</td>
<td class="nump">1,285,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions', window );">Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases</a></td>
<td class="nump">$ 27,900<span></span>
</td>
<td class="nump">$ 22,900<span></span>
</td>
<td class="nump">$ 13,700<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_CommonStockCapitalSharesReservedForFutureIssuance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Aggregate number of common shares reserved for future issuance.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.29)<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockCapitalSharesReservedForFutureIssuance</td>
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<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>instant</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockNumberOfSharesParValueAndOtherDisclosuresAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CommonStockSharesAuthorized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum number of common shares permitted to be issued by an entity's charter and bylaws.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockSharesAuthorized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
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<td>instant</td>
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</table></div>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total number of common shares of an entity that have been sold or granted to shareholders (includes common shares that were issued, repurchased and remain in the treasury). These shares represent capital invested by the firm's shareholders and owners, and may be all or only a portion of the number of shares authorized. Shares issued include shares outstanding and shares held in the treasury.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockSharesIssued</td>
</tr>
<tr>
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<tr>
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<td>xbrli:sharesItemType</td>
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<tr>
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<td>na</td>
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<tr>
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</div></td></tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares of common stock outstanding. Common stock represent the ownership interest in a corporation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CommonStockSharesOutstanding</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
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<td>xbrli:sharesItemType</td>
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<tr>
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<tr>
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</tr>
</table></div>
</div></td></tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PreferredStockNumberOfSharesParValueAndOtherDisclosuresAbstract</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum number of nonredeemable preferred shares (or preferred stock redeemable solely at the option of the issuer) permitted to be issued by an entity's charter and bylaws.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PreferredStockSharesAuthorized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
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<td><strong> Balance Type:</strong></td>
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<td>instant</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PreferredStockSharesIssued">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total number of nonredeemable preferred shares (or preferred stock redeemable solely at the option of the issuer) issued to shareholders (includes related preferred shares that were issued, repurchased, and remain in the treasury). May be all or portion of the number of preferred shares authorized. Excludes preferred shares that are classified as debt.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PreferredStockSharesIssued</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>na</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Aggregate share number for all nonredeemable preferred stock (or preferred stock redeemable solely at the option of the issuer) held by stockholders. Does not include preferred shares that have been repurchased.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PreferredStockSharesOutstanding</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow from issuance of shares under share-based compensation arrangement. Issuance includes, but is not limited to, exercise of stock options and similar instruments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=SL79508275-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfSharesUnderIncentiveAndShareBasedCompensationPlansIncludingStockOptions</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodSharesShareBasedCompensationGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Gross number of shares (or other type of equity) issued during the period as a result of any equity-based compensation plan other than an employee stock ownership plan (ESOP). Shares issued could result from the issuance of restricted stock, the exercise of stock options, stock issued under employee stock purchase plans, and/or other employee benefit plans.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Stock Plans (Details)<br></strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="1">12 Months Ended</th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
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<th class="th">
<div>Jun. 30, 2009 </div>
<div>shares</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>Installment </div>
<div>$ / shares </div>
<div>shares</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>shares</div>
</th>
<th class="th">
<div>May 31, 2017 </div>
<div>shares</div>
</th>
<th class="th">
<div>Apr. 30, 2017 </div>
<div>shares</div>
</th>
<th class="th">
<div>Jun. 30, 2015 </div>
<div>shares</div>
</th>
<th class="th">
<div>May 31, 2015 </div>
<div>shares</div>
</th>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_StockOptionMember', window );">Stock Options [Member]</a></td>
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</td>
<td class="text">&#160;<span></span>
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</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<td class="text">&#160;<span></span>
</td>
<td class="nump">11,311,000<span></span>
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<td class="nump">9,397,000<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">6,071,000<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_StockOptionPlan1989Member', window );">1989 Stock Option Plan [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized', window );">Number of shares authorized (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod', window );">Award term</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">7 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Number of options outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">848,753<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>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber', window );">Number of options exercisable (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">831,656<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant', window );">Number of shares available for grant (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">42,925<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_StockOptionPlan1989Member', window );">1989 Stock Option Plan [Member] | One Year from Date of Grant [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage', window );">Vesting percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member', window );">2011 Equity Incentive Plan [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized', window );">Number of shares authorized (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">16,000,000<span></span>
</td>
<td class="nump">11,000,000<span></span>
</td>
<td class="nump">11,000,000<span></span>
</td>
<td class="nump">5,500,000<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Number of options outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">9,705,441<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber', window );">Number of options exercisable (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">4,801,904<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant', window );">Number of shares available for grant (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3,340,351<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers', window );">Period before change of control when vesting will accelerate for executive officers</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">3 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers', window );">Period after change of control when vesting will accelerate for executive officers</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">12 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber', window );">Number of awards outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,183,154<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member', window );">2011 Equity Incentive Plan [Member] | Stock Options [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">2 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member', window );">2011 Equity Incentive Plan [Member] | Restricted Stock Units [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">4 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member', window );">2011 Equity Incentive Plan [Member] | Restricted Stock Units [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1', window );">Vesting period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">3 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_NonemployeeDirectorsStockOptionPlan2002Member', window );">2002 Non-Employee Directors' Stock Option Plan [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized', window );">Number of shares authorized (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,000,000<span></span>
</td>
<td class="nump">1,200,000<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod', window );">Award term</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">10 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Number of options outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">757,750<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber', window );">Number of options exercisable (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">437,750<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant', window );">Number of shares available for grant (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">420,762<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber', window );">Number of awards outstanding (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">63,099<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_NonemployeeDirectorsStockOptionPlan2002Member', window );">2002 Non-Employee Directors' Stock Option Plan [Member] | One Year from Date of Grant [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable', window );">Number of equal annual installments over which options become exercisable | Installment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PlanNameAxis=ions_EmployeeStockPurchasePlanMember', window );">Employee Stock Purchase Plan [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract', window );"><strong>Stock Plans [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized', window );">Number of shares authorized (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3,674,596<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant', window );">Number of shares available for grant (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">774,816<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized', window );">Number of additional shares reserved for issuance (in shares)</a></td>
<td class="nump">150,000<span></span>
</td>
<td class="nump">150,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardMaximumEmployeeSubscriptionRate', window );">Maximum percentage of employee compensation used to purchase shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardPurchasePriceOfCommonStockPercent', window );">Percentage of fair market value used to determine purchase price of stock</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">85.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod', window );">Purchase period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">6 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod', window );">Holding period for purchased stock</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">6 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans', window );">Shares purchased and issued under ESPP (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">43,416<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeStockOwnershipPlanESOPWeightedAveragePurchasePriceOfSharesPurchased', window );">Purchase price (in dollars per share) | $ / shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 39.03<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></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_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of equal annual installments over which options become exercisable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfEqualAnnualInstallmentsOverWhichOptionsBecomeExercisable</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time after a change of control of the Company when vesting will accelerate for options and RSUs outstanding as of the termination date for executive officers, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PeriodAfterChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers</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_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time before a change of control of the Company when vesting will accelerate for options and RSUs outstanding as of the termination date for executive officers, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PeriodBeforeChangeOfControlWhenVestingWillAccelerateForExecutiveOfficers</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Represents the holding period from the date of purchase for stock purchased under the plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardHoldingPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Represents the period to purchase common stock under the plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardPurchasePeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeStockOwnershipPlanESOPWeightedAveragePurchasePriceOfSharesPurchased">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average purchase price of capital shares purchased through an employee stock ownership plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeStockOwnershipPlanESOPWeightedAveragePurchasePriceOfSharesPurchased</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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_ShareBasedArrangementsToObtainGoodsAndServicesAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedArrangementsToObtainGoodsAndServicesAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
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</tr>
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<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period which an employee's right to exercise an award is no longer contingent on satisfaction of either a service condition, market condition or a performance condition, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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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_ShareBasedCompensationArrangementByShareBasedPaymentAwardMaximumEmployeeSubscriptionRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The highest percentage of annual salary that an employee is permitted to utilize with respect to the plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardMaximumEmployeeSubscriptionRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of equity instruments other than options outstanding, including both vested and non-vested instruments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(i)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNonOptionEquityInstrumentsOutstandingNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of additional shares authorized for issuance under an established share-based compensation plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum number of shares (or other type of equity) originally approved (usually by shareholders and board of directors), net of any subsequent amendments and adjustments, for awards under the equity-based compensation plan. As stock or unit options and equity instruments other than options are awarded to participants, the shares or units remain authorized and become reserved for issuance under outstanding awards (not necessarily vested).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The difference between the maximum number of shares (or other type of equity) authorized for issuance under the plan (including the effects of amendments and adjustments), and the sum of: 1) the number of shares (or other type of equity) already issued upon exercise of options or other equity-based awards under the plan; and 2) shares (or other type of equity) reserved for issuance on granting of outstanding awards, net of cancellations and forfeitures, if applicable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of shares into which fully or partially vested stock options outstanding as of the balance sheet date can be currently converted under the option plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iii)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of options outstanding, including both vested and non-vested options.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(i)-(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of vesting of share-based compensation awards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardAwardVestingRightsPercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period from grant date that an equity-based award expires, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (a)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardExpirationPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardPurchasePriceOfCommonStockPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Purchase price of common stock expressed as a percentage of its fair value.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardPurchasePriceOfCommonStockPercent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares issued during the period as a result of an employee stock purchase plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=27012166&amp;loc=d3e187085-122770<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardTypeAxis=us-gaap_StockOptionMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=us-gaap_StockOptionMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=us-gaap_RestrictedStockUnitsRSUMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PlanNameAxis=ions_StockOptionPlan1989Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PlanNameAxis=ions_StockOptionPlan1989Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_VestingAxis=us-gaap_ShareBasedCompensationAwardTrancheOneMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_VestingAxis=us-gaap_ShareBasedCompensationAwardTrancheOneMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PlanNameAxis=ions_EquityIncentivePlan2011Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_RangeAxis=srt_MinimumMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_RangeAxis=srt_MinimumMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PlanNameAxis=ions_NonemployeeDirectorsStockOptionPlan2002Member">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PlanNameAxis=ions_NonemployeeDirectorsStockOptionPlan2002Member</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_PlanNameAxis=ions_EmployeeStockPurchasePlanMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PlanNameAxis=ions_EmployeeStockPurchasePlanMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
</div>
</body>
</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>92
<FILENAME>R60.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6820258160">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Stock Option Activity (Details) - Stock Options [Member] - USD ($)<br> $ / shares in Units, shares in Thousands, $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingRollForward', window );"><strong>Number of Shares [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Outstanding at beginning of period (in shares)</a></td>
<td class="nump">9,397<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross', window );">Granted (in shares)</a></td>
<td class="nump">3,518<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised', window );">Exercised (in shares)</a></td>
<td class="num">(1,064)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod', window );">Cancelled/forfeited/expired (in shares)</a></td>
<td class="num">(540)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber', window );">Outstanding at end of period (in shares)</a></td>
<td class="nump">11,311<span></span>
</td>
<td class="nump">9,397<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber', window );">Exercisable at end of period (in shares)</a></td>
<td class="nump">6,071<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePriceRollforward', window );"><strong>Weighted Average Exercise Price Per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice', window );">Outstanding at beginning of period (in dollars per share)</a></td>
<td class="nump">$ 44.52<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice', window );">Granted (in dollars per share)</a></td>
<td class="nump">48.40<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice', window );">Exercised (in dollars per share)</a></td>
<td class="nump">17.78<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsForfeituresInPeriodWeightedAverageExercisePrice', window );">Cancelled/forfeited/expired (in dollars per share)</a></td>
<td class="nump">52.47<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice', window );">Outstanding at end of period (in dollars per share)</a></td>
<td class="nump">47.85<span></span>
</td>
<td class="nump">$ 44.52<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableWeightedAverageExercisePrice', window );">Exercisable at end of period (in dollars per share)</a></td>
<td class="nump">$ 46.83<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsAdditionalDisclosuresAbstract', window );"><strong>Average Remaining Contractual Term, Aggregate Intrinsic Value and Other [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2', window );">Average remaining contractual term, outstanding at end of period</a></td>
<td class="text">4 years 4 months 28 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1', window );">Average remaining contractual term, exercisable at end of period</a></td>
<td class="text">3 years 2 months 19 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue', window );">Aggregate intrinsic value, outstanding at end of period</a></td>
<td class="nump">$ 93,663<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableIntrinsicValue1', window );">Aggregate intrinsic value, exercisable at end of period</a></td>
<td class="nump">$ 63,756<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue', window );">Weighted average fair value of options granted (in dollars per share)</a></td>
<td class="nump">$ 25.49<span></span>
</td>
<td class="nump">$ 25.42<span></span>
</td>
<td class="nump">$ 26.72<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue', window );">Intrinsic value of options exercised</a></td>
<td class="nump">$ 34,800<span></span>
</td>
<td class="nump">$ 49,500<span></span>
</td>
<td class="nump">$ 28,000<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromStockOptionsExercised', window );">Cash received from exercise of stock options</a></td>
<td class="nump">$ 18,900<span></span>
</td>
<td class="nump">$ 21,200<span></span>
</td>
<td class="nump">$ 12,600<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue', window );">Weighted-average fair value of options exercised (in dollars per share)</a></td>
<td class="nump">$ 50.50<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="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract', window );"><strong>Unrecognized Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions', window );">Unrecognized compensation expense related to non-vested stock options</a></td>
<td class="nump">$ 118,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1', window );">Weighted average period for recognition</a></td>
<td class="text">1 year 2 months 12 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted average grant-date fair value of options exercised during the reporting period as calculated by applying the disclosed option pricing methodology.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average period over which unrecognized compensation is expected to be recognized for equity-based compensation plans, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Unrecognized cost of unvested options awarded to employees as compensation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromStockOptionsExercised">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cash inflow from exercise of stock options granted under share-based compensation arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=SL79508275-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromStockOptionsExercised</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsAdditionalDisclosuresAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsAdditionalDisclosuresAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of shares into which fully or partially vested stock options outstanding as of the balance sheet date can be currently converted under the option plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iii)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableWeightedAverageExercisePrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted-average price as of the balance sheet date at which grantees can acquire the shares reserved for issuance on vested portions of options outstanding and currently exercisable under the stock option plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iii)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableWeightedAverageExercisePrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of accumulated difference between fair value of underlying shares on dates of exercise and exercise price on options exercised (or share units converted) into shares.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (d)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For presentations that combine terminations, the number of shares under options that were cancelled during the reporting period as a result of occurrence of a terminating event specified in contractual agreements pertaining to the stock option plan or that expired.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iv)(3)-(4)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresAndExpirationsInPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Gross number of share options (or share units) granted during the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted average grant-date fair value of options granted during the reporting period as calculated by applying the disclosed option pricing methodology.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (d)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingIntrinsicValue">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount by which the current fair value of the underlying stock exceeds the exercise price of options outstanding.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of options outstanding, including both vested and non-vested options.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(i)-(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average price at which grantees can acquire the shares reserved for issuance under the stock option plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(i)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingWeightedAverageExercisePrice</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average price at which option holders acquired shares when converting their stock options into shares.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average price at which grantees could have acquired the underlying shares with respect to stock options that were terminated.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average per share amount at which grantees can acquire shares of common stock by exercise of options.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice</td>
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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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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of difference between fair value of the underlying shares reserved for issuance and exercise price of vested portions of options outstanding and currently exercisable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average remaining contractual term for vested portions of options outstanding and currently exercisable or convertible, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsExercisableWeightedAverageRemainingContractualTerm1</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average remaining contractual term for option awards outstanding, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (e)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsOutstandingWeightedAverageRemainingContractualTerm2</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of share options (or share units) exercised during the current period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iv)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=27012166&amp;loc=d3e187085-122770<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<DESCRIPTION>IDEA: XBRL DOCUMENT
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6805726576">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Restricted Stock Unit Activity (Details) - Restricted Stock Units [Member] - USD ($)<br> $ / shares in Units, shares in Thousands, $ in Millions</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedRollForward', window );"><strong>Number of Shares [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber', window );">Non-vested at beginning of period (in shares)</a></td>
<td class="nump">863<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod', window );">Granted (in shares)</a></td>
<td class="nump">789<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriod', window );">Vested (in shares)</a></td>
<td class="num">(324)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeitedInPeriod', window );">Cancelled/forfeited (in shares)</a></td>
<td class="num">(82)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber', window );">Non-vested at end of period (in shares)</a></td>
<td class="nump">1,246<span></span>
</td>
<td class="nump">863<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValueRollForward', window );"><strong>Weighted Average Grant Date Fair Value per Share [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValue', window );">Non-vested at beginning of period (in dollars per share)</a></td>
<td class="nump">$ 49.55<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriodWeightedAverageGrantDateFairValue', window );">Granted (in dollars per share)</a></td>
<td class="nump">51.06<span></span>
</td>
<td class="nump">$ 48.88<span></span>
</td>
<td class="nump">$ 41.79<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriodWeightedAverageGrantDateFairValue', window );">Vested (in dollars per share)</a></td>
<td class="nump">50.21<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeituresWeightedAverageGrantDateFairValue', window );">Cancelled/forfeited (in dollars per share)</a></td>
<td class="nump">51.59<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValue', window );">Non-vested at end of period (in dollars per share)</a></td>
<td class="nump">$ 50.20<span></span>
</td>
<td class="nump">$ 49.55<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract', window );"><strong>Unrecognized Compensation Expense [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions', window );">Unrecognized compensation cost related to non-vested RSUs</a></td>
<td class="nump">$ 27.9<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1', window );">Weighted average period for recognition</a></td>
<td class="text">1 year 4 months 24 days<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average period over which unrecognized compensation is expected to be recognized for equity-based compensation plans, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Unrecognized cost of unvested share-based awards, other than options, awarded to employees as compensation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (i)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedShareBasedAwardsOtherThanOptions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeitedInPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of equity-based payment instruments, excluding stock (or unit) options, that were forfeited during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(1)(iv)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeitedInPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeituresWeightedAverageGrantDateFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average fair value as of the grant date of equity-based award plans other than stock (unit) option plans that were not exercised or put into effect as a result of the occurrence of a terminating event.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(iii)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsForfeituresWeightedAverageGrantDateFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of grants made during the period on other than stock (or unit) option plans (for example, phantom stock or unit plan, stock or unit appreciation rights plan, performance target plan).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(iii)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriodWeightedAverageGrantDateFairValue">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted average fair value at grant date for nonvested equity-based awards issued during the period on other than stock (or unit) option plans (for example, phantom stock or unit plan, stock or unit appreciation rights plan, performance target plan).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(iii)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriodWeightedAverageGrantDateFairValue</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of non-vested equity-based payment instruments, excluding stock (or unit) options, that validly exist and are outstanding as of the balance sheet date.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(i)-(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedNumber</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted average fair value of nonvested awards on equity-based plans excluding option plans (for example, phantom stock or unit plan, stock or unit appreciation rights plan, revenue or profit achievement stock award plan) for which the employer is contingently obligated to issue equity instruments or transfer assets to an employee who has not yet satisfied service or performance criteria necessary to gain title to proceeds from the sale of the award or underlying shares or units.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(i)-(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsNonvestedWeightedAverageGrantDateFairValue</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of equity-based payment instruments, excluding stock (or unit) options, that vested during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(iii)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsVestedInPeriod</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The weighted average fair value as of grant date pertaining to an equity-based award plan other than a stock (or unit) option plan for which the grantee gained the right during the reporting period, by satisfying service and performance requirements, to receive or retain shares or units, other instruments, or cash in accordance with the terms of the arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)(2)(iii)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Stock-based Compensation Expense (Details) - USD ($)<br> $ in Thousands</strong></div></th>
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<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
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<td class="nump">76,557<span></span>
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<td class="nump">64,521<span></span>
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<td class="nump">55,099<span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Represents the expense recognized during the period arising from equity-based compensation arrangements (for example, shares of stock, unit, stock options or other equity instruments) with employees, directors and certain consultants qualifying for treatment as employees.</p></div>
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<td style="white-space:nowrap;">us-gaap_IncomeStatementLocationAxis=ions_ResearchDevelopmentAndPatentMember</td>
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<td style="white-space:nowrap;">us-gaap_IncomeStatementLocationAxis=us-gaap_SellingGeneralAndAdministrativeExpensesMember</td>
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<td style="white-space:nowrap;">srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember</td>
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<head>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6803713712">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Stockholders' Equity, Stock-based Valuation Information (Details)<br></strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockOptionMember', window );">Employee Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate', window );">Risk-free interest rate</a></td>
<td class="nump">2.40%<span></span>
</td>
<td class="nump">1.80%<span></span>
</td>
<td class="nump">1.50%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate', window );">Dividend yield</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate', window );">Volatility</a></td>
<td class="nump">63.00%<span></span>
</td>
<td class="nump">65.90%<span></span>
</td>
<td class="nump">58.70%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1', window );">Expected life</a></td>
<td class="text">4 years 7 months 6 days<span></span>
</td>
<td class="text">4 years 6 months<span></span>
</td>
<td class="text">4 years 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="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=ions_BoardOfDirectorStockOptionMember', window );">Board of Director Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate', window );">Risk-free interest rate</a></td>
<td class="nump">2.80%<span></span>
</td>
<td class="nump">2.20%<span></span>
</td>
<td class="nump">1.30%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate', window );">Dividend yield</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate', window );">Volatility</a></td>
<td class="nump">61.50%<span></span>
</td>
<td class="nump">61.20%<span></span>
</td>
<td class="nump">53.10%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1', window );">Expected life</a></td>
<td class="text">6 years 7 months 6 days<span></span>
</td>
<td class="text">6 years 7 months 6 days<span></span>
</td>
<td class="text">6 years 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="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockMember', window );">ESPP [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate', window );">Risk-free interest rate</a></td>
<td class="nump">1.80%<span></span>
</td>
<td class="nump">0.80%<span></span>
</td>
<td class="nump">0.40%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate', window );">Dividend yield</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate', window );">Volatility</a></td>
<td class="nump">47.30%<span></span>
</td>
<td class="nump">59.90%<span></span>
</td>
<td class="nump">86.40%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1', window );">Expected life</a></td>
<td class="text">6 months<span></span>
</td>
<td class="text">6 months<span></span>
</td>
<td class="text">6 months<span></span>
</td>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Employee Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate', window );">Risk-free interest rate</a></td>
<td class="nump">2.80%<span></span>
</td>
<td class="nump">1.90%<span></span>
</td>
<td class="nump">1.60%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate', window );">Dividend yield</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate', window );">Volatility</a></td>
<td class="nump">77.10%<span></span>
</td>
<td class="nump">79.50%<span></span>
</td>
<td class="nump">71.40%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1', window );">Expected life</a></td>
<td class="text">6 years 29 days<span></span>
</td>
<td class="text">6 years 22 days<span></span>
</td>
<td class="text">6 years 29 days<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Board of Director Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract', window );"><strong>Weighted-Average Assumptions [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate', window );">Risk-free interest rate</a></td>
<td class="nump">2.90%<span></span>
</td>
<td class="nump">1.90%<span></span>
</td>
<td class="nump">2.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate', window );">Dividend yield</a></td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate', window );">Volatility</a></td>
<td class="nump">78.20%<span></span>
</td>
<td class="nump">79.40%<span></span>
</td>
<td class="nump">79.60%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1', window );">Expected life</a></td>
<td class="text">6 years 5 months 1 day<span></span>
</td>
<td class="text">6 years 3 months<span></span>
</td>
<td class="text">6 years 29 days<span></span>
</td>
</tr>
</table>
<div style="display: none;">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsAndMethodologyAbstract</td>
</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>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The estimated dividend rate (a percentage of the share price) to be paid (expected dividends) to holders of the underlying shares over the option's term.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(iii)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate</td>
</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>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The risk-free interest rate assumption that is used in valuing an option on its own shares.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(iv)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Weighted average expected volatility rate of share-based compensation awards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(ii)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsWeightedAverageVolatilityRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Expected term of share-based compensation awards, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (f)(2)(i)<br> -URI http://asc.fasb.org/extlink&amp;oid=109197908&amp;loc=d3e5070-113901<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 718<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 14.D.2)<br> -URI http://asc.fasb.org/extlink&amp;oid=115993241&amp;loc=d3e301413-122809<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1</td>
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<tr>
<td 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>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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</table></div>
</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_EmployeeStockOptionMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=us-gaap_EmployeeStockOptionMember</td>
</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>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_AwardTypeAxis=ions_BoardOfDirectorStockOptionMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=ions_BoardOfDirectorStockOptionMember</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_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_AwardTypeAxis=us-gaap_EmployeeStockMember</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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<td><strong> Balance Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember</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>
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<DOCUMENT>
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<html>
<head>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6810683280">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Loss Before Income Tax (Benefit) Expense (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxDisclosureAbstract', window );"><strong>Income Taxes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic', window );">United States</a></td>
<td class="num">$ (69,576)<span></span>
</td>
<td class="num">$ (5,289)<span></span>
</td>
<td class="num">$ (57,466)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign', window );">Foreign</a></td>
<td class="num">(6,580)<span></span>
</td>
<td class="num">(11,474)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments', window );">Loss before income tax benefit (expense)</a></td>
<td class="num">$ (76,156)<span></span>
</td>
<td class="num">$ (16,763)<span></span>
</td>
<td class="num">$ (57,466)<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of earnings or loss from continuing operations before income taxes that is attributable to domestic operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08.(h)(1)(i))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesDomestic</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of earnings or loss from continuing operations before income taxes that is attributable to foreign operations, which is defined as Income or Loss generated from operations located outside the entity's country of domicile.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08.(h)(1)(i))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesForeign</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>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_IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of income (loss) from continuing operations before deduction of income tax expense (benefit) and income (loss) attributable to noncontrolling interest, and addition of income (loss) from equity method investments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08.(h)(1)(i))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<td><strong> Period Type:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxDisclosureAbstract</td>
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<DOCUMENT>
<TYPE>XML
<SEQUENCE>97
<FILENAME>R65.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6972284192">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Income Tax (Benefit) Expense (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract', window );"><strong>Current [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CurrentFederalTaxExpenseBenefit', window );">Federal</a></td>
<td class="nump">$ 438<span></span>
</td>
<td class="num">$ (7,460)<span></span>
</td>
<td class="nump">$ 1,067<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CurrentStateAndLocalTaxExpenseBenefit', window );">State</a></td>
<td class="num">(1,442)<span></span>
</td>
<td class="nump">1,246<span></span>
</td>
<td class="nump">1,867<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CurrentForeignTaxExpenseBenefit', window );">Foreign</a></td>
<td class="nump">374<span></span>
</td>
<td class="nump">234<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CurrentIncomeTaxExpenseBenefit', window );">Total current income tax (benefit) expense</a></td>
<td class="num">(630)<span></span>
</td>
<td class="num">(5,980)<span></span>
</td>
<td class="nump">2,934<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredIncomeTaxExpenseBenefitContinuingOperationsAbstract', window );"><strong>Deferred [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredFederalIncomeTaxExpenseBenefit', window );">Federal</a></td>
<td class="num">(290,511)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredStateAndLocalIncomeTaxExpenseBenefit', window );">State</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredIncomeTaxExpenseBenefit', window );">Total deferred income tax (benefit) expense</a></td>
<td class="num">(290,511)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Income tax (benefit) expense</a></td>
<td class="num">$ (291,141)<span></span>
</td>
<td class="num">$ (5,980)<span></span>
</td>
<td class="nump">$ 2,934<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CurrentFederalTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current federal tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32639-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CurrentFederalTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CurrentForeignTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current foreign income tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32639-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08.(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CurrentForeignTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CurrentIncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current income tax expense (benefit) pertaining to taxable income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&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 9<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32639-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CurrentIncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CurrentIncomeTaxExpenseBenefitContinuingOperationsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<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_CurrentStateAndLocalTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current state and local tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32639-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CurrentStateAndLocalTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredFederalIncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred federal income tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32639-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredFederalIncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredIncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred income tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32639-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredIncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredIncomeTaxExpenseBenefitContinuingOperationsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredIncomeTaxExpenseBenefitContinuingOperationsAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<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_DeferredStateAndLocalIncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred state and local tax expense (benefit) pertaining to income (loss) from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB Topic 6.I.7)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 9<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32639-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredStateAndLocalIncomeTaxExpenseBenefit</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current income tax expense (benefit) and deferred income tax expense (benefit) pertaining to continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (h)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109238882&amp;loc=d3e38679-109324<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><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>
</div>
</body>
</html>
</TEXT>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6805529664">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Reconciliation of Statutory to Effective Tax Rate (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefitContinuingOperationsIncomeTaxReconciliationAbstract', window );"><strong>Reconciliation Between Effective and Statutory Tax Rate [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments', window );">Pre-tax loss</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (76,156)<span></span>
</td>
<td class="num">$ (16,763)<span></span>
</td>
<td class="num">$ (57,466)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate', window );">Statutory rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(15,993)<span></span>
</td>
<td class="num">(5,867)<span></span>
</td>
<td class="num">(20,113)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationStateAndLocalIncomeTaxes', window );">State income tax net of federal benefit</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(2,202)<span></span>
</td>
<td class="nump">820<span></span>
</td>
<td class="nump">95<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationForeignIncomeTaxRateDifferential', window );">Foreign</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,735<span></span>
</td>
<td class="nump">4,299<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance', window );">Net change in valuation allowance</a></td>
<td class="nump">$ 332,100<span></span>
</td>
<td class="num">(277,924)<span></span>
</td>
<td class="num">(86,296)<span></span>
</td>
<td class="nump">46,402<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount', window );">Net operating loss expiration</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">8,864<span></span>
</td>
<td class="nump">3,987<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="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationDrugLicensingGainAmount', window );">TEGSEDI licensing gain</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">59,583<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationTaxCredits', window );">Tax credits</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(73,362)<span></span>
</td>
<td class="num">(32,769)<span></span>
</td>
<td class="num">(26,954)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationPriorYearIncomeTaxes', window );">Deferred tax true-up</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">9,947<span></span>
</td>
<td class="nump">4,848<span></span>
</td>
<td class="nump">2,591<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationChangeInEnactedTaxRate', window );">Tax rate change</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(1,808)<span></span>
</td>
<td class="nump">114,832<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="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationAmount', window );">Non-deductible compensation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3,154<span></span>
</td>
<td class="nump">1,575<span></span>
</td>
<td class="nump">825<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationNondeductibleExpenseOther', window );">Other non-deductible items</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(569)<span></span>
</td>
<td class="nump">2,548<span></span>
</td>
<td class="nump">324<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationDeconsolidationAdjustmentForSubsidiaryAtIPOAmount', window );">Akcea deconsolidation adjustment at IPO</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">469<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost', window );">Stock-based compensation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(4,199)<span></span>
</td>
<td class="num">(14,337)<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationOtherAdjustments', window );">Other</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,633<span></span>
</td>
<td class="num">(89)<span></span>
</td>
<td class="num">(236)<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxExpenseBenefit', window );">Income tax (benefit) expense</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (291,141)<span></span>
</td>
<td class="num">$ (5,980)<span></span>
</td>
<td class="nump">$ 2,934<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateContinuingOperationsTaxRateReconciliationAbstract', window );"><strong>Reconciliation Between Effective and Statutory Tax Rate Percentage [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate', window );">Statutory rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">21.00%<span></span>
</td>
<td class="nump">35.00%<span></span>
</td>
<td class="nump">35.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationStateAndLocalIncomeTaxes', window );">State income tax net of federal benefit</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2.90%<span></span>
</td>
<td class="num">(4.90%)<span></span>
</td>
<td class="num">(0.20%)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationForeignIncomeTaxRateDifferential', window );">Foreign</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(2.30%)<span></span>
</td>
<td class="num">(25.60%)<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationChangeInDeferredTaxAssetsValuationAllowance', window );">Net change in valuation allowance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">364.90%<span></span>
</td>
<td class="nump">514.80%<span></span>
</td>
<td class="num">(80.70%)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossPercent', window );">Net operating loss expiration</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(11.60%)<span></span>
</td>
<td class="num">(23.80%)<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationDrugLicensingGainPercent', window );">TEGSEDI licensing gain</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(78.20%)<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationTaxCredits', window );">Tax credits</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">96.30%<span></span>
</td>
<td class="nump">195.50%<span></span>
</td>
<td class="nump">46.90%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationPriorYearIncomeTaxes', window );">Deferred tax true-up</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(13.10%)<span></span>
</td>
<td class="num">(28.90%)<span></span>
</td>
<td class="num">(4.50%)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationChangeInEnactedTaxRate', window );">Tax rate change</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2.40%<span></span>
</td>
<td class="num">(685.00%)<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationPercent', window );">Non-deductible compensation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(4.10%)<span></span>
</td>
<td class="num">(9.40%)<span></span>
</td>
<td class="num">(1.40%)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseOther', window );">Other nondeductible items</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.70%<span></span>
</td>
<td class="num">(15.20%)<span></span>
</td>
<td class="num">(0.60%)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_EffectiveIncomeTaxRateReconciliationDeconsolidationAdjustmentForSubsidiaryAtIPOPercent', window );">Akcea deconsolidation adjustment at IPO</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="num">(2.80%)<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseShareBasedCompensationCost', window );">Stock-based compensation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">5.50%<span></span>
</td>
<td class="nump">85.50%<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationOtherAdjustments', window );">Other</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(2.10%)<span></span>
</td>
<td class="nump">0.50%<span></span>
</td>
<td class="nump">0.40%<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateContinuingOperations', window );">Effective rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">382.30%<span></span>
</td>
<td class="nump">35.70%<span></span>
</td>
<td class="num">(5.10%)<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationDeconsolidationAdjustmentForSubsidiaryAtIPOAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to an adjustment for the deconsolidation of a subsidiary from the consolidated federal income tax return on the date of the subsidiary's Initial Public Offering (IPO).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationDeconsolidationAdjustmentForSubsidiaryAtIPOAmount</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_EffectiveIncomeTaxRateReconciliationDeconsolidationAdjustmentForSubsidiaryAtIPOPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to an adjustment for the deconsolidation of a subsidiary from the consolidated federal income tax return on the date of the subsidiary's Initial Public Offering (IPO).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationDeconsolidationAdjustmentForSubsidiaryAtIPOPercent</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>num: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_EffectiveIncomeTaxRateReconciliationDrugLicensingGainAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to licensing gain on TEGSEDI.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationDrugLicensingGainAmount</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_EffectiveIncomeTaxRateReconciliationDrugLicensingGainPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to licensing gain on TEGSEDI.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationDrugLicensingGainPercent</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>num: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_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to the expiration of net operating loss carryforwards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossAmount</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_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to the expiration of net operating loss carryforwards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationExpirationOfNetOperatingLossPercent</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>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to compensation in excess of $1 million paid to any "covered employee" of the corporation under Section 162(m) of the Tax Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationPercent">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to compensation in excess of $1 million paid to any "covered employee" of the corporation under Section 162(m) of the Tax Act.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseExcessCompensationPercent</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateContinuingOperations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of current income tax expense (benefit) and deferred income tax expense (benefit) pertaining to continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08.(h)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateContinuingOperations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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</tr>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateContinuingOperationsTaxRateReconciliationAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateContinuingOperationsTaxRateReconciliationAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of domestic federal statutory tax rate applicable to pretax income (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationChangeInDeferredTaxAssetsValuationAllowance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to changes in the valuation allowance for deferred tax assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationChangeInDeferredTaxAssetsValuationAllowance</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationChangeInEnactedTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to changes in the income tax rates.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationChangeInEnactedTaxRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationForeignIncomeTaxRateDifferential">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations applicable to statutory income tax expense (benefit) outside of the country of domicile.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to other nondeductible expenses.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseOther</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to equity-based compensation costs.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationNondeductibleExpenseShareBasedCompensationCost</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to other adjustments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationOtherAdjustments</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EffectiveIncomeTaxRateReconciliationPriorYearIncomeTaxes">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to revisions of previously reported income tax expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationPriorYearIncomeTaxes</td>
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<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_EffectiveIncomeTaxRateReconciliationStateAndLocalIncomeTaxes">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations applicable to state and local income tax expense (benefit), net of federal tax expense (benefit).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationStateAndLocalIncomeTaxes</td>
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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_EffectiveIncomeTaxRateReconciliationTaxCredits">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to tax credits. Including, but not limited to, research credit, foreign tax credit, investment tax credit, and other tax credits.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationTaxCredits</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_IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of income (loss) from continuing operations before deduction of income tax expense (benefit) and income (loss) attributable to noncontrolling interest, and addition of income (loss) from equity method investments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08.(h)(1)(i))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesMinorityInterestAndIncomeLossFromEquityMethodInvestments</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of current income tax expense (benefit) and deferred income tax expense (benefit) pertaining to continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (h)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 20<br> -Section 45<br> -Paragraph 2<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109238882&amp;loc=d3e38679-109324<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to increase (decrease) in the valuation allowance for deferred tax assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=84176650&amp;loc=d3e32123-109318<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationChangeInEnactedTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations, attributable to increase (decrease) in the income tax rates.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 15<br> -URI http://asc.fasb.org/extlink&amp;oid=84176650&amp;loc=d3e32059-109318<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationChangeInEnactedTaxRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationForeignIncomeTaxRateDifferential">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to foreign income tax expense (benefit).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationForeignIncomeTaxRateDifferential</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<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_IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of income tax expense or benefit for the period computed by applying the domestic federal statutory tax rates to pretax income from continuing operations.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationNondeductibleExpenseOther">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to other nondeductible expenses.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationNondeductibleExpenseOther</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to nondeductible equity-based compensation costs.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationOtherAdjustments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to other adjustments.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationOtherAdjustments</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<td><strong> Period Type:</strong></td>
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</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationPriorYearIncomeTaxes">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to revisions of previously reported income tax expense (benefit).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationPriorYearIncomeTaxes</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationStateAndLocalIncomeTaxes">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to state and local income tax expense (benefit).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.4-08(h)(2))<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e23780-122690<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationStateAndLocalIncomeTaxes</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationTaxCredits">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to tax credits. Including, but not limited to, research credit, foreign tax credit, investment tax credit, and other tax credits.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationTaxCredits</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6797453072">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Deferred Tax Assets and Liabilities (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsGrossAbstract', window );"><strong>Deferred Tax Assets [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsOperatingLossCarryforwards', window );">Net operating loss carryovers</a></td>
<td class="nump">$ 89,717<span></span>
</td>
<td class="nump">$ 89,717<span></span>
</td>
<td class="nump">$ 153,575<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsTaxCreditCarryforwardsResearch', window );">R&amp;D credits</a></td>
<td class="nump">313,652<span></span>
</td>
<td class="nump">313,652<span></span>
</td>
<td class="nump">240,290<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsDeferredIncome', window );">Deferred revenue</a></td>
<td class="nump">27,381<span></span>
</td>
<td class="nump">27,381<span></span>
</td>
<td class="nump">54,302<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost', window );">Stock-based compensation</a></td>
<td class="nump">61,027<span></span>
</td>
<td class="nump">61,027<span></span>
</td>
<td class="nump">40,090<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsGoodwillAndIntangibleAssets', window );">Intangible and capital assets</a></td>
<td class="nump">49,007<span></span>
</td>
<td class="nump">49,007<span></span>
</td>
<td class="nump">672<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsOther', window );">Other</a></td>
<td class="nump">8,275<span></span>
</td>
<td class="nump">8,275<span></span>
</td>
<td class="nump">12,164<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsGross', window );">Total deferred tax assets</a></td>
<td class="nump">549,059<span></span>
</td>
<td class="nump">549,059<span></span>
</td>
<td class="nump">501,093<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxLiabilitiesAbstract', window );"><strong>Deferred Tax Liabilities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxLiabilitiesFinancingArrangements', window );">Convertible debt</a></td>
<td class="num">(24,018)<span></span>
</td>
<td class="num">(24,018)<span></span>
</td>
<td class="num">(32,391)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance', window );">Net deferred tax asset</a></td>
<td class="nump">525,041<span></span>
</td>
<td class="nump">525,041<span></span>
</td>
<td class="nump">468,702<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsValuationAllowance', window );">Valuation allowance</a></td>
<td class="num">(234,245)<span></span>
</td>
<td class="num">(234,245)<span></span>
</td>
<td class="num">(468,702)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="reu">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DeferredTaxAssetsLiabilitiesNet', window );">Total net deferred tax assets and liabilities</a></td>
<td class="nump">290,796<span></span>
</td>
<td class="nump">290,796<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance', window );">One-time non-cash tax benefit related to reversal of valuation allowance</a></td>
<td class="nump">$ 332,100<span></span>
</td>
<td class="num">$ (277,924)<span></span>
</td>
<td class="num">$ (86,296)<span></span>
</td>
<td class="nump">$ 46,402<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_OperatingLossCarryforwardsUtilizationPeriod', window );">Utilization period for net operating loss carryforwards and tax credit carryforwards</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">3 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ValuationAllowancesAndReservesPeriodIncreaseDecrease', window );">Decrease in valuation allowance</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (234,500)<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_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Represents the net amount of deferred tax assets (before reduction for valuation allowance) and liabilities as of the balance sheet date, which result from applying the applicable enacted tax rate to net temporary differences and carryforwards pertaining to assets or liabilities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DeferredTaxAssetsLiabilitiesNetBeforeValuationAllowance</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_OperatingLossCarryforwardsUtilizationPeriod">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time before operating loss carryforwards and tax credit carryforwards will be utilized, in PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_OperatingLossCarryforwardsUtilizationPeriod</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsDeferredIncome">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible temporary differences from deferred income.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32632-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 25<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=115928272&amp;loc=d3e28680-109314<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32621-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsDeferredIncome</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsGoodwillAndIntangibleAssets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible temporary differences from intangible assets including goodwill.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsGoodwillAndIntangibleAssets</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsGross">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible temporary differences and carryforwards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32537-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsGross</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsGrossAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsGrossAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsLiabilitiesNet">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after allocation of valuation allowances and deferred tax liability, of deferred tax asset attributable to deductible differences and carryforwards, without jurisdictional netting.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32537-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsLiabilitiesNet</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DeferredTaxAssetsOperatingLossCarryforwards">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible operating loss carryforwards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32621-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32632-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 25<br> -Paragraph 20<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=115928272&amp;loc=d3e28680-109314<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsOperatingLossCarryforwards</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, before allocation of valuation allowance, of deferred tax asset attributable to deductible temporary differences, classified as other.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 25<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=115928272&amp;loc=d3e28680-109314<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32632-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32621-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsOther</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible research tax credit carryforwards.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32632-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32559-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32621-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsTaxCreditCarryforwardsResearch</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount before allocation of valuation allowances of deferred tax asset attributable to deductible temporary differences from share-based compensation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 25<br> -Paragraph 20<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=115928272&amp;loc=d3e28680-109314<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32632-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32621-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred tax assets for which it is more likely than not that a tax benefit will not be realized.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32537-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxAssetsValuationAllowance</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DeferredTaxLiabilitiesAbstract</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of deferred tax liability attributable to taxable temporary differences from financing arrangements.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32621-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 25<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=115928272&amp;loc=d3e28680-109314<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32632-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of the difference between reported income tax expense (benefit) and expected income tax expense (benefit) computed by applying the domestic federal statutory income tax rates to pretax income (loss) from continuing operations attributable to increase (decrease) in the valuation allowance for deferred tax assets.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=84176650&amp;loc=d3e32123-109318<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) in valuation and qualifying accounts and reserves.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2009/role/commonPracticeRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 235<br> -SubTopic 10<br> -Section S99<br> -Paragraph 4<br> -Subparagraph (SX 210.12-09)<br> -URI http://asc.fasb.org/extlink&amp;oid=26873400&amp;loc=d3e24092-122690<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6804340688">
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<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Income Taxes, Tax Credit Carryforwards (Details)<br> $ in Millions</strong></div></th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_InternalRevenueServiceIRSMember', window );">Federal [Member]</a></td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLossCarryforwards', window );">Net operating loss carryforwards</a></td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_InternalRevenueServiceIRSMember', window );">Federal [Member] | Research and Development [Member]</a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TaxCreditCarryforwardLineItems', window );"><strong>Tax Credit Carryforwards [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TaxCreditCarryforwardAmount', window );">Tax credit carryforwards</a></td>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_CaliforniaFranchiseTaxBoardMember', window );">California [Member]</a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLossCarryforwardsLineItems', window );"><strong>Operating Loss Carryforwards [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingLossCarryforwards', window );">Net operating loss carryforwards</a></td>
<td class="nump">808.7<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_CaliforniaFranchiseTaxBoardMember', window );">California [Member] | Research and Development [Member]</a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TaxCreditCarryforwardLineItems', window );"><strong>Tax Credit Carryforwards [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TaxCreditCarryforwardAmount', window );">Tax credit carryforwards</a></td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of operating loss carryforward, before tax effects, available to reduce future taxable income under enacted tax laws.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32559-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLossCarryforwards</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_OperatingLossCarryforwardsLineItems">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Line items represent financial concepts included in a table. These concepts are used to disclose reportable information associated with domain members defined in one or many axes to the table.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingLossCarryforwardsLineItems</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TaxCreditCarryforwardAmount">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of the tax credit carryforward, before tax effects, available to reduce future taxable income under enacted tax laws.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32559-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TaxCreditCarryforwardAmount</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TaxCreditCarryforwardLineItems">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Line items represent financial concepts included in a table. These concepts are used to disclose reportable information associated with domain members defined in one or many axes to the table.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TaxCreditCarryforwardLineItems</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_InternalRevenueServiceIRSMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_InternalRevenueServiceIRSMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TaxCreditCarryforwardAxis=us-gaap_ResearchMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TaxCreditCarryforwardAxis=us-gaap_ResearchMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_CaliforniaFranchiseTaxBoardMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxAuthorityNameAxis=us-gaap_CaliforniaFranchiseTaxBoardMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</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>
<TYPE>XML
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<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6803161968">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Tax Act (Details) - USD ($)<br> $ in Millions</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncomeTaxDisclosureAbstract', window );"><strong>Income Taxes [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate', window );">U.S. federal corporate tax rate</a></td>
<td class="nump">21.00%<span></span>
</td>
<td class="nump">35.00%<span></span>
</td>
<td class="nump">35.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_TaxCutsAndJobsActOf2017IncompleteAccountingChangeInTaxRateProvisionalIncomeTaxExpenseBenefit', window );">Provisional tax expense for impact of change in tax rate on deferred tax assets under the Tax Act</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 107.3<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_TaxCutsAndJobsActOf2017IncompleteAccountingChangeInTaxRateProvisionalIncomeTaxExpenseBenefit">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of reasonable estimate for income tax expense (benefit) for remeasurement of deferred tax from change in tax rate pursuant to Tax Cuts and Jobs Act of 2017 for which accounting for tax effect is incomplete.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_TaxCutsAndJobsActOf2017IncompleteAccountingChangeInTaxRateProvisionalIncomeTaxExpenseBenefit</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_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of domestic federal statutory tax rate applicable to pretax income (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SAB TOPIC 6.I)<br> -URI http://asc.fasb.org/extlink&amp;oid=34349781&amp;loc=d3e330036-122817<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 12<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32687-109319<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 13<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32698-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_EffectiveIncomeTaxRateReconciliationAtFederalStatutoryIncomeTaxRate</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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_IncomeTaxDisclosureAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncomeTaxDisclosureAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<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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<DOCUMENT>
<TYPE>XML
<SEQUENCE>102
<FILENAME>R70.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6972117216">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Income Taxes, Gross Unrecognized Tax Benefits (Details) - USD ($)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ReconciliationOfUnrecognizedTaxBenefitsExcludingAmountsPertainingToExaminedTaxReturnsRollForward', window );"><strong>Gross Unrecognized Tax Benefits [Roll Forward]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefits', window );">Beginning balance of unrecognized tax benefits</a></td>
<td class="nump">$ 78,014<span></span>
</td>
<td class="nump">$ 66,999<span></span>
</td>
<td class="nump">$ 51,257<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsDecreasesResultingFromSettlementsWithTaxingAuthorities', window );">Settlement of prior period tax positions</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="num">(4,033)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions', window );">Decrease for prior period tax positions</a></td>
<td class="num">(12,814)<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions', window );">Increase for prior period tax positions</a></td>
<td class="nump">0<span></span>
</td>
<td class="nump">1,520<span></span>
</td>
<td class="nump">7,928<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions', window );">Increase for current period tax positions</a></td>
<td class="nump">3,101<span></span>
</td>
<td class="nump">9,495<span></span>
</td>
<td class="nump">11,847<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefits', window );">Ending balance of unrecognized tax benefits</a></td>
<td class="nump">68,301<span></span>
</td>
<td class="nump">$ 78,014<span></span>
</td>
<td class="nump">$ 66,999<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate', window );">Unrecognized tax benefits that could impact effective tax rate, if recognized</a></td>
<td class="nump">55,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense', window );">Interest and penalties on unrecognized tax benefits</a></td>
<td class="nump">$ 0<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_ReconciliationOfUnrecognizedTaxBenefitsExcludingAmountsPertainingToExaminedTaxReturnsRollForward">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>A roll forward is a reconciliation of a concept from the beginning of a period to the end of a period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ReconciliationOfUnrecognizedTaxBenefitsExcludingAmountsPertainingToExaminedTaxReturnsRollForward</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefits">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of unrecognized tax benefits.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10B<br> -URI http://asc.fasb.org/extlink&amp;oid=84176650&amp;loc=SL37586934-109318<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefits</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of decrease in unrecognized tax benefits resulting from tax positions taken in prior period tax returns.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsDecreasesResultingFromPriorPeriodTaxPositions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefitsDecreasesResultingFromSettlementsWithTaxingAuthorities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of decrease in unrecognized tax benefits resulting from settlements with taxing authorities.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (a)(3)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsDecreasesResultingFromSettlementsWithTaxingAuthorities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of expense for interest on an underpayment of income taxes and penalties related to a tax position claimed or expected to be claimed in the tax return.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=d3e32718-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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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_UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase in unrecognized tax benefits resulting from tax positions that have been or will be taken in current period tax return.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (a)(2)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromCurrentPeriodTaxPositions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase in unrecognized tax benefits resulting from tax positions taken in prior period tax returns.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsIncreasesResultingFromPriorPeriodTaxPositions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The total amount of unrecognized tax benefits that, if recognized, would affect the effective tax rate.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 740<br> -SubTopic 10<br> -Section 50<br> -Paragraph 15A<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=84230637&amp;loc=SL6600010-109319<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Biogen (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="5">1 Months Ended</th>
<th class="th" colspan="4">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
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<tr>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Jul. 31, 2016 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>May 31, 2015 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Sep. 30, 2013 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Dec. 31, 2012 </div>
<div>USD ($) </div>
<div>PerformanceObligation </div>
<div>Target </div>
<div>Program</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($) </div>
<div>Drug </div>
<div>Country </div>
<div>Target</div>
</th>
<th class="th">
<div>Sep. 30, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Jun. 30, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Sep. 30, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($) </div>
<div>Drug </div>
<div>Country </div>
<div>Target</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Apr. 30, 2018 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 91,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 599,674<span></span>
</td>
<td class="nump">$ 514,179<span></span>
</td>
<td class="nump">$ 372,776<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="nump">$ 233,362<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">233,362<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_SPINRAZARoyaltiesMember', window );">SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">237,930<span></span>
</td>
<td class="nump">112,540<span></span>
</td>
<td class="nump">883<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember', window );">Licensing and Other Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">14,755<span></span>
</td>
<td class="nump">7,474<span></span>
</td>
<td class="nump">21,884<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 344,752<span></span>
</td>
<td class="nump">394,165<span></span>
</td>
<td class="nump">350,009<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBiogenMember', window );">Biogen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases', window );">Number of additional drugs in clinical development to treat neurodegenerative diseases | Drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">375,000<span></span>
</td>
<td class="nump">263,100<span></span>
</td>
<td class="nump">$ 249,700<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="nump">$ 93,600<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">580,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 580,900<span></span>
</td>
<td class="nump">$ 93,600<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBiogenMember', window );">Biogen [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">63.00%<span></span>
</td>
<td class="nump">51.00%<span></span>
</td>
<td class="nump">67.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBiogenMember', window );">Biogen [Member] | SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 237,900<span></span>
</td>
<td class="nump">$ 112,500<span></span>
</td>
<td class="nump">$ 900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBiogenMember', window );">Biogen [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">137,100<span></span>
</td>
<td class="nump">150,600<span></span>
</td>
<td class="nump">$ 248,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember', window );">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>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax', window );">Cumulative revenue earned</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 785,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 785,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember', window );">SPINRAZA [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfCountriesWhereDrugIsApprovedForUse', window );">Number of countries where SPINRAZA is approved for use | Country</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">40<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">40<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfDrug', window );">Royalty percentage received on net sales of drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">11.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember', window );">SPINRAZA [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfDrug', window );">Royalty percentage received on net sales of drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember', window );">SPINRAZA [Member] | SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax', window );">Cumulative revenue earned</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 350,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 350,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember', window );">SPINRAZA [Member] | Licensing and Other Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2012WithBiogenMember', window );">SPINRAZA [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax', window );">Cumulative revenue earned</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">435,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 435,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 90,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2017WithBiogenMember', window );">New Antisense Drugs for the Treatment of SMA [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfDrug', window );">Royalty percentage received on net sales of drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones', window );">Maximum amount of payments receivable for license fees and substantive milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,200,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">80,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">80,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones', window );">Maximum amount of payments receivable for commercialization milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">180,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">180,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones', window );">Maximum amount of payments receivable for sales milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">800,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">800,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2018WithBiogenMember', window );">2018 Strategic Neurology [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfDrug', window );">Royalty percentage received on net sales of drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfTargets', window );">Number of targets | Target</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 375,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 7,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 7,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 552,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments', window );">Maximum amount of payments receivable per drug for substantive milestone payments</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">270,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 270,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_TermOfCollaborationAgreement', window );">Term of collaboration agreement</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">10 years<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceivedIncludingPurchaseOfStock', window );">Upfront payment received, including purchase of stock</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfCommonStock', window );">Proceeds from issuance of common stock</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 625,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PercentageCashPremiumPaidOnSharesPurchased', window );">Percentage cash premium paid on shares purchased</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PremiumPaidOnSharesPurchased', window );">Premium paid on shares purchased</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 177,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPriceAdditions', window );">Milestone payments received and added to transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember', window );">2013 Strategic Neurology [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">210,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 210,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfDrugsCurrentlyBeingAdvanced', window );">Number of drugs currently being advanced | Drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">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="nump">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>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember', window );">2013 Strategic Neurology [Member] | Licensing and Other Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 35,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember', window );">2013 Strategic Neurology [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentsIncludedInTransactionPriceForPerformanceObligation', window );">Payments included in transaction price for performance obligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">145,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 145,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">5,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInSeptember2013WithBiogenMember', window );">2013 Strategic Neurology [Member] | Antisense Molecule [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones', window );">Maximum amount of payments receivable for license fees and substantive milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">260,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">260,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">130,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">130,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember', window );">Neurology [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">58,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">58,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfTargets', window );">Number of targets | Target</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized', window );">Number of programs under which drugs are to be developed and commercialized | Program</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">7,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">7,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments', window );">Maximum amount of payments receivable per program for license fee and substantive milestone payments</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">210,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">210,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones', window );">Maximum amount of payments receivable per program for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones', window );">Maximum amount of payments receivable per program for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">130,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">130,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPriceAdditions', window );">Milestone payments received and added to transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithBiogenMember', window );">Neurology [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentsIncludedInTransactionPriceForPerformanceObligation', window );">Payments included in transaction price for performance obligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 40,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 40,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativeRevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for commercialization milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for license fees and substantive milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForSalesMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for sales milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForSalesMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable per drug for substantive milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivablePerDrugForSubstantiveMilestonePayments</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_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable per drug or program for development milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForDevelopmentMilestones</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_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable per drug or program for license fees and/or substantive milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForLicenseFeesAndSubstantiveMilestonePayments</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_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable per drug or program for regulatory milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NextPotentialPayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialPayment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of additional drugs in clinical development to treat neurodegenerative diseases under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfAdditionalDrugsInClinicalDevelopmentToTreatNeurodegenerativeDiseases</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfCountriesWhereDrugIsApprovedForUse">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of countries where the drug is approved for treatment in patients.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfCountriesWhereDrugIsApprovedForUse</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfDrugsCurrentlyBeingAdvanced">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of drugs currently being advanced under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfDrugsCurrentlyBeingAdvanced</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of programs under which drugs are to be developed and commercialized under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfTargets">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of targets for the research and development of drugs under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfTargets</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PaymentsIncludedInTransactionPriceForPerformanceObligation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total payments received since inception of the collaboration agreement included in the transaction price for the performance obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentsIncludedInTransactionPriceForPerformanceObligation</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_PercentageCashPremiumPaidOnSharesPurchased">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage cash premium paid per share of the Company's common stock under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PercentageCashPremiumPaidOnSharesPurchased</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PremiumPaidOnSharesPurchased">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash premium paid on the purchase of the Company's common stock under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PremiumPaidOnSharesPurchased</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPriceAdditions">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The additional amount of consideration the Company earned under the collaboration agreement that is added to the transaction price.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPriceAdditions</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RoyaltyPercentageReceivedOnNetSalesOfDrug">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Royalty percentage received on the net sales of a drug by a collaboration partner under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RoyaltyPercentageReceivedOnNetSalesOfDrug</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>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_TermOfCollaborationAgreement">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Term of the collaboration agreement, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_TermOfCollaborationAgreement</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:durationItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceivedIncludingPurchaseOfStock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The total amount of the upfront payment received, including the purchase of shares of the Company's stock, under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceivedIncludingPurchaseOfStock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13531-108611<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 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13537-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromIssuanceOfCommonStock">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from the additional capital contribution to the entity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfCommonStock</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_SPINRAZARoyaltiesMember</td>
</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_LicensingAndOtherRoyaltiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBiogenMember">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, AstraZeneca (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">1 Months Ended</th>
<th class="th" colspan="3">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
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<th class="th">
<div>Jul. 31, 2015 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
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<th class="th">
<div>May 31, 2015 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2012 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($) </div>
<div>Drug </div>
<div>Program</div>
</th>
<th class="th">
<div>Sep. 30, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Mar. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($) </div>
<div>Drug</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Mar. 31, 2014 </div>
<div>PerformanceObligation</div>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="nump">$ 91,200<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="nump">$ 514,179<span></span>
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<td class="nump">$ 372,776<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">233,362<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">344,752<span></span>
</td>
<td class="nump">394,165<span></span>
</td>
<td class="nump">$ 350,009<span></span>
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<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember', window );">AstraZeneca [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 40,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 40,100<span></span>
</td>
<td class="nump">$ 57,700<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember', window );">AstraZeneca [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="nump">4.00%<span></span>
</td>
<td class="nump">11.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember', window );">AstraZeneca [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 120,700<span></span>
</td>
<td class="nump">$ 21,600<span></span>
</td>
<td class="nump">$ 41,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember', window );">Cardiac, Renal and Metabolic Diseases [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements', window );">Number of drugs that can be licensed under option in collaboration agreements | Drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="nump">$ 65,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones', window );">Minimum amount of payments receivable for license fees and substantive milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 4,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 4,000,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,900,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,900,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">165,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">165,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 65,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember', window );">Cardiac, Renal and Metabolic Diseases [Member] | IONIS-AZ5-2.5 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember', window );">Cardiac, Renal and Metabolic Diseases [Member] | IONIS-AZ6-2.5 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJuly2015WithAstraZenecaMember', window );">Cardiac, Renal and Metabolic Diseases [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentsIncludedInTransactionPriceForPerformanceObligation', window );">Payments included in transaction price for performance obligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">90,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">90,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember', window );">Oncology [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 31,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones', window );">Minimum amount of payments receivable for license fees and substantive milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">450,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">450,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">152,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">152,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">275,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">275,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">125,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">125,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialPayment', window );">Next prospective payment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfProgramsAdvanced', window );">Number of programs advanced | Program</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 31,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfObligationsFullySatisified', window );">Number of obligations fully satisfied | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember', window );">Oncology [Member] | Danvatirsen [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">17,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember', window );">Oncology [Member] | Undisclosed Program [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember', window );">Oncology [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 7,600<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The minimum amount of payments receivable for license fees and substantive milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NextPotentialPayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialPayment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of drugs that can be licensed by the partner(s) under their respective collaboration agreements.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfDrugsThatCanBeLicensedUnderOptionInCollaborationAgreements</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfObligationsFullySatisified">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of obligations fully satisfied under the collaboration agreement for which revenue is recognized over the period of performance.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfObligationsFullySatisified</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfProgramsAdvanced">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of programs advanced under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfProgramsAdvanced</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PaymentsIncludedInTransactionPriceForPerformanceObligation">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Total payments received since inception of the collaboration agreement included in the transaction price for the performance obligation.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentsIncludedInTransactionPriceForPerformanceObligation</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_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13531-108611<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 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13537-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsAstraZenecaMember</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>
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</table></div>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- 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_SalesRevenueGoodsNetMember</td>
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<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
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<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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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="top.Show.hideAR();">X</a></td></tr>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2012WithAstraZenecaMember</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>105
<FILENAME>R73.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
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<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6803208912">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Bayer (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2">1 Months Ended</th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>Feb. 28, 2017 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>May 31, 2015 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Jun. 30, 2015 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 91,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 599,674<span></span>
</td>
<td class="nump">$ 514,179<span></span>
</td>
<td class="nump">$ 372,776<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">233,362<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">344,752<span></span>
</td>
<td class="nump">394,165<span></span>
</td>
<td class="nump">$ 350,009<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBayerMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 4,300<span></span>
</td>
<td class="nump">$ 9,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBayerMember', window );">Bayer [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">13.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsBayerMember', window );">Bayer [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 5,000<span></span>
</td>
<td class="nump">$ 67,100<span></span>
</td>
<td class="nump">$ 5,400<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones', window );">Maximum amount of payments receivable for license fees and substantive milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">385,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">125,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones', window );">Maximum amount of payments receivable for commercialization milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 110,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement', window );">Royalty percentage received on gross margins of both drugs combined</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 175,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialMilestonePayment', window );">Next prospective milestone</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember', window );">Bayer [Member] | IONIS-FXI [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">91,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember', window );">Bayer [Member] | R&amp;D Services for IONIS-FXI [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">4,300<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember', window );">Bayer [Member] | IONIS-FXI API [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 4,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMay2015WithBayerMember', window );">Bayer [Member] | R&amp;D Services for IONIS-FXI-L [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 10,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember', window );">Bayer [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentReceivedForAdvancingPrograms', window );">Payment received for advancing programs</a></td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations', window );">Number of new performance obligations | PerformanceObligation</a></td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember', window );">Bayer [Member] | IONIS-FXI-L [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 64,900<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations', window );">Number of new performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementAmendedInFebruary2017WithBayerMember', window );">Bayer [Member] | R&amp;D Services for IONIS-FXI-L [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations', window );">Number of new performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for commercialization milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for license fees and substantive milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones</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_NextPotentialMilestonePayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential milestone payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialMilestonePayment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PaymentReceivedForAdvancingPrograms">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of payments received during the period for advancing programs under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentReceivedForAdvancingPrograms</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of new performance obligations identified under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfNewPerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The royalty percentage received on gross margins of drug(s) under the collaborative arrangement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RoyaltyPercentageReceivedOnGrossMarginsOfDrugsUnderCollaborationAgreement</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>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13531-108611<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 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13537-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6806375056">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, GSK (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="2">1 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>May 31, 2015 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Mar. 31, 2010 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($) </div>
<div>Drug</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 91,200<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 599,674<span></span>
</td>
<td class="nump">$ 514,179<span></span>
</td>
<td class="nump">$ 372,776<span></span>
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</tr>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">233,362<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 344,752<span></span>
</td>
<td class="nump">394,165<span></span>
</td>
<td class="nump">$ 350,009<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember', window );">GSK [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 35,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfAntisenseDrugsInDevelopment', window );">Number of antisense drugs in development | Drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones', window );">Maximum amount of payments receivable for license fees and substantive milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 262,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">47,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">120,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones', window );">Maximum amount of payments receivable for commercialization milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">70,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 35,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember', window );">GSK [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0.00%<span></span>
</td>
<td class="nump">3.00%<span></span>
</td>
<td class="nump">5.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember', window );">GSK [Member] | Minimum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 162,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember', window );">GSK [Member] | Maximum [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialMilestonePayment', window );">Next prospective milestone</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInMarch2010WithGSKMember', window );">GSK [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 1,600<span></span>
</td>
<td class="nump">$ 14,800<span></span>
</td>
<td class="nump">$ 17,500<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for commercialization milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for license fees and substantive milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NextPotentialMilestonePayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential milestone payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialMilestonePayment</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_NumberOfAntisenseDrugsInDevelopment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of antisense drugs in development designed to reduce the production of viral proteins associated with hepatitis B virus, or HBV, infection under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfAntisenseDrugsInDevelopment</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13531-108611<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 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13537-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Janssen Biotech, Inc. (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="5">1 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1">17 Months Ended</th>
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<th class="th">
<div>Jan. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Nov. 30, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Jul. 31, 2016 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>May 31, 2015 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2014 </div>
<div>USD ($) </div>
<div>PerformanceObligation </div>
<div>Program</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
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<th class="th">
<div>Nov. 30, 2017 </div>
<div>USD ($)</div>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">14,755<span></span>
</td>
<td class="nump">7,474<span></span>
</td>
<td class="nump">21,884<span></span>
</td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">344,752<span></span>
</td>
<td class="nump">394,165<span></span>
</td>
<td class="nump">$ 350,009<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember', window );">Janssen Biotech, Inc. [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized', window );">Number of programs under which drugs are to be developed and commercialized | Program</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">3<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 35,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones', window );">Minimum amount of payments receivable for license fees and substantive milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">800,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">175,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">440,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones', window );">Maximum amount of payments receivable for commercialization milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">180,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialMilestonePayment', window );">Next prospective milestone</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">5,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 35,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember', window );">Janssen Biotech, Inc. [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">7.00%<span></span>
</td>
<td class="nump">7.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember', window );">Janssen Biotech, Inc. [Member] | Licensing and Other Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 15,000<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember', window );">Janssen Biotech, Inc. [Member] | IONIS-JBI1-2.5 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 5,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember', window );">Janssen Biotech, Inc. [Member] | IONIS-JBI2-2.5 [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 5,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInDecember2014WithJanssenBiotechIncMember', window );">Janssen Biotech, Inc. [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 6,600<span></span>
</td>
<td class="nump">$ 36,000<span></span>
</td>
<td class="nump">$ 24,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for commercialization milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The minimum amount of payments receivable for license fees and substantive milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MinimumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones</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_NextPotentialMilestonePayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential milestone payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialMilestonePayment</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_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of programs under which drugs are to be developed and commercialized under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfProgramsUnderWhichDrugsAreToBeDevelopedAndCommercialized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13531-108611<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 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13537-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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_LicensingAndOtherRoyaltiesMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6805144992">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Roche (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="3">1 Months Ended</th>
<th class="th" colspan="1">2 Months Ended</th>
<th class="th" colspan="2">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>Oct. 31, 2018 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>May 31, 2015 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Apr. 30, 2013 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>Mar. 01, 2019 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 91,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 599,674<span></span>
</td>
<td class="nump">$ 514,179<span></span>
</td>
<td class="nump">$ 372,776<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 233,362<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">233,362<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">344,752<span></span>
</td>
<td class="nump">394,165<span></span>
</td>
<td class="nump">$ 350,009<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsRocheMember', window );">Roche [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 72,600<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">$ 72,600<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsRocheMember', window );">Roche [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">11.00%<span></span>
</td>
<td class="nump">3.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementsAndLicensingAgreementsRocheMember', window );">Roche [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 8,300<span></span>
</td>
<td class="nump">$ 55,700<span></span>
</td>
<td class="nump">$ 10,700<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember', window );">Huntington's Disease [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MilestonePaymentsReceived', window );">Milestone payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 3,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones', window );">Maximum amount of payments receivable for license fees and substantive milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">365,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">365,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">70,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">70,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">170,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">170,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones', window );">Maximum amount of payments receivable for commercialization milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">80,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">80,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped', window );">Maximum amount of payment receivable for each additional drug developed</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">136,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">136,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CumulativePaymentsReceived', window );">Cumulative payments received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">112,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">112,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialMilestonePayment', window );">Next prospective milestone</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="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 custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 30,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember', window );">Huntington's Disease [Member] | IONIS-HTT [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 45,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember', window );">Huntington's Disease [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>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 35,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember', window );">IONIS-FB-L for Complement-Mediated Diseases [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones', window );">Maximum amount of payments receivable for license fees and substantive milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">684,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">684,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NextPotentialMilestonePayment', window );">Next prospective milestone</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 20,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 20,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="nump">1<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfDrug', window );">Royalty percentage received on net sales of drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_CumulativePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cumulative amount of payments received under the collaboration agreement as of the end of the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CumulativePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for each additional drug developed under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentReceivableForEachAdditionalDrugDeveloped</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for commercialization milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for license fees and substantive milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForLicenseFeesAndSubstantiveMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MilestonePaymentsReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of milestone payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MilestonePaymentsReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NextPotentialMilestonePayment">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The next potential milestone payment to be earned under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NextPotentialMilestonePayment</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_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RoyaltyPercentageReceivedOnNetSalesOfDrug">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Royalty percentage received on the net sales of a drug by a collaboration partner under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RoyaltyPercentageReceivedOnNetSalesOfDrug</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>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13531-108611<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 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13537-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ContractWithCustomerLiability</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td>na</td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- 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_CollaborativeArrangementsAndLicensingAgreementsRocheMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInApril2013WithRocheMember</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_HttMember</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInOctober2018WithRocheMember</td>
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<td></td>
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<DOCUMENT>
<TYPE>XML
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<DESCRIPTION>IDEA: XBRL DOCUMENT
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<head>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6819153696">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, Novartis (Details)<br> $ in Thousands, shares in Millions</strong></div></th>
<th class="th" colspan="3">1 Months Ended</th>
<th class="th" colspan="1">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th">
<div>Feb. 27, 2019 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Jul. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>May 31, 2015 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Mar. 31, 2017 </div>
<div>USD ($) </div>
<div>PerformanceObligation </div>
<div>shares</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Mar. 01, 2019 </div>
<div>USD ($) </div>
<div>shares</div>
</th>
<th class="th">
<div>Jan. 31, 2017 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfPrivatePlacement', window );">Proceeds from sale of common stock to Novartis in a private placement</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="nump">$ 50,000<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 91,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">599,674<span></span>
</td>
<td class="nump">514,179<span></span>
</td>
<td class="nump">372,776<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">233,362<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SubsequentEventTypeAxis=us-gaap_SubsequentEventMember', window );">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>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug', window );">Sublicense fee to be paid in stock by Akcea for license of AKCEA-AP)(a)-L</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug', window );">Additional shares of Akcea stock to be received for license of AKCEA-APO(a)-L (in shares) | shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2.8<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">344,752<span></span>
</td>
<td class="nump">394,165<span></span>
</td>
<td class="nump">$ 350,009<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember', window );">Novartis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StockIssuedDuringPeriodSharesNewIssues', window );">Shares issued (in shares) | shares</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.6<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid', window );">Proceeds from sale of common stock</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 100,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AdditionalAmountOfCommonStockRequiredToBePurchased', window );">Additional amount of common stock required to be purchased</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 50,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">4<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 108,400<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PremiumReceivedOnSharesIssued', window );">Premium received on shares issued</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">28,400<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture', window );">Potential premium received if common stock is purchased in the future</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">5,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 28,800<span></span>
</td>
<td class="nump">$ 70,700<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember', window );">Novartis [Member] | Revenue [Member] | Strategic Partner [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">8.00%<span></span>
</td>
<td class="nump">8.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember', window );">Novartis [Member] | R&amp;D Services for AKCEA-APO(a)-L [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">64,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember', window );">Novartis [Member] | Delivery of AKCEA-APO(a)-L [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember', window );">Novartis [Member] | R&amp;D Services for AKCEA-APOCIII-L [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">40,100<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember', window );">Novartis [Member] | Delivery of AKCEA-APOCIII-L [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerTransactionPrice', window );">Transaction price</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,800<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember', window );">Novartis [Member] | R&amp;D [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 50,600<span></span>
</td>
<td class="nump">$ 43,400<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Novartis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_UpfrontPaymentReceived', window );">Upfront payment received</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">75,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PortionOfUpfrontPaymentRetained', window );">Portion of upfront payment retained</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">60,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PortionOfUpfrontPaymentPaidAsASublicenseFee', window );">Portion of upfront payment paid as a sublicense fee</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LicenseFeePaidPerDrug', window );">License fee receivable per drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 150,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee', window );">Percentage of license fees, milestone payments and royalties paid as sublicense fee</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">50.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_AdditionalAmountOfCommonStockRequiredToBePurchased', window );">Additional amount of common stock required to be purchased</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 50,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromIssuanceOfPrivatePlacement', window );">Proceeds from sale of common stock to Novartis in a private placement</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 50,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Novartis [Member] | License Fees [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>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 150,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Novartis [Member] | AKCEA-APO(a)-L [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForMilestones', window );">Maximum amount of payments receivable for milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 675,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">290,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones', window );">Maximum amount of payments receivable for commercialization milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 360,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnSalesOfDrug', window );">Royalty percentage received on sales of drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Novartis [Member] | AKCEA-APOCIII-L [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForMilestones', window );">Maximum amount of payments receivable for milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 530,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones', window );">Maximum amount of payments receivable for development milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">25,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones', window );">Maximum amount of payments receivable for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">240,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones', window );">Maximum amount of payments receivable for commercialization milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 265,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnSalesOfDrug', window );">Royalty percentage received on sales of drug</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_AdditionalAmountOfCommonStockRequiredToBePurchased">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The additional amount of common stock the collaboration partner is required to purchase under a Stock Purchase Agreement (SPA) in conjunction with the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_AdditionalAmountOfCommonStockRequiredToBePurchased</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_CollaborativeArrangementAndLicensingAgreementAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LicenseFeePaidPerDrug">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The license fee payment receivable per drug under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LicenseFeePaidPerDrug</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for commercialization milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForCommercializationMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for development milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForDevelopmentMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable for regulatory milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivableForRegulatoryMilestones</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage of license fees, milestone payments and royalties paid as sublicense fee under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PercentageOfLicenseFeesMilestonePaymentsAndRoyaltiesPaidAsSublicenseFee</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>num: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_PortionOfUpfrontPaymentPaidAsASublicenseFee">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of the upfront payment received during the period under the collaboration agreement that was paid as a sublicense fee.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PortionOfUpfrontPaymentPaidAsASublicenseFee</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_PortionOfUpfrontPaymentRetained">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of the upfront payment received during the period under the collaboration agreement that was retained by the entity.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PortionOfUpfrontPaymentRetained</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_PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The potential premium received if common stock is purchased in the future under a Stock Purchase Agreement (SPA) in conjunction with the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PotentialPremiumReceivedIfCommonStockIsPurchasedInTheFuture</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PremiumReceivedOnSharesIssued">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The total amount of the premium received over the trading price of common stock at the time of purchase.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PremiumReceivedOnSharesIssued</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow from the sale of common stock, including the premium paid for the purchase of common stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_ProceedsFromSaleOfCommonStockIncludingPremiumPaid</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueFromContractWithCustomerTransactionPrice">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of consideration the Company is eligible to earn under the collaboration agreement, including any variable consideration.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerTransactionPrice</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RoyaltyPercentageReceivedOnSalesOfDrug">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Royalty percentage received on the sales of a drug by a collaboration partner under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RoyaltyPercentageReceivedOnSalesOfDrug</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>num: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_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of additional shares of stock to be received from Akcea Therapeutics, Inc. as a sublicense fee as result of Novartis licensing AKCEA-APO(a)-L.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_SharesToBeReceivedFromSubsidiaryForLicenseOfDrug</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of the sublicense fee to be paid in Akcea common stock as a result of Novartis licensing AKCEA-APO(a)-L.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_SublicenseFeeToBePaidBySubsidiaryForLicenseOfDrug</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_UpfrontPaymentReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of upfront payments received during the period under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_UpfrontPaymentReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13531-108611<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 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13537-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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_ProceedsFromIssuanceOfPrivatePlacement">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The cash inflow associated with the amount received from entity's raising of capital via private rather than public placement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 14<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3255-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromIssuanceOfPrivatePlacement</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_StockIssuedDuringPeriodSharesNewIssues">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of new stock issued during the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(29))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21463-112644<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.3-04)<br> -URI http://asc.fasb.org/extlink&amp;oid=27012166&amp;loc=d3e187085-122770<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StockIssuedDuringPeriodSharesNewIssues</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SubsequentEventTypeAxis=us-gaap_SubsequentEventMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SubsequentEventTypeAxis=us-gaap_SubsequentEventMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
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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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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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</tr>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInJanuary2017WithNovartisMember</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_SalesRevenueGoodsNetMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_SalesRevenueGoodsNetMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CustomerConcentrationRiskMember</td>
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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>
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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_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentServicesForAKCEAAPOALMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentServicesForAKCEAAPOALMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_DeliveryOfAKCEAAPOALMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_DeliveryOfAKCEAAPOALMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<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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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentServicesForAKCEAAPOCIIILMember</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_DeliveryOfAKCEAAPOCIIILMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=us-gaap_LicenseMember</td>
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<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_AKCEAAPOALMember</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_AKCEAAPOCIIILMember</td>
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<DOCUMENT>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6800327008">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, PTC Therapeutics (Details)<br> $ in Thousands</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="3">12 Months Ended</th>
</tr>
<tr>
<th class="th">
<div>Aug. 31, 2018 </div>
<div>USD ($) </div>
<div>PerformanceObligation</div>
</th>
<th class="th">
<div>May 31, 2015 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Sep. 30, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
</th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 91,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 599,674<span></span>
</td>
<td class="nump">$ 514,179<span></span>
</td>
<td class="nump">$ 372,776<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">233,362<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember', window );">PTC Therapeutics [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations', window );">Number of separate performance obligations | PerformanceObligation</a></td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ContractWithCustomerLiability', window );">Deferred revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">$ 0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember', window );">PTC Therapeutics [Member] | Sublicense Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 7,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | PTC Therapeutics [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentReceivableUnderLicenseAgreement', window );">Payment receivable under license agreement</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">26,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProceedsFromLicenseFeesReceived', window );">Payment received under license agreement</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 12,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval', window );">Payment to be received on earlier of FDA or EMA approval of WAYLIVRA</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones', window );">Maximum amount of payments receivable per drug for regulatory milestones</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 8,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner', window );">Royalty percentage received on net sales of each drug in Latin America from PTC</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">20.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_PeriodBeforeCollaborationPartnerPaysRoyaltiesOnNetSalesOfProductAfterFirstCommercialSaleInBrazil', window );">Period before PTC pays royalties on net sales of product after first commercial sale in Brazil</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">12 months<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties', window );">Minimum revenue recognized in Latin America by PTC before paying royalties</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 10,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | PTC Therapeutics [Member] | License Fees [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_CollaborativeArrangementAndLicensingAgreementAbstract', window );"><strong>Collaborative Arrangement and Licensing Agreement [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 12,000<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
</table>
<div style="display: none;">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments receivable per drug or program for regulatory milestone payments under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsReceivablePerDrugOrProgramForRegulatoryMilestones</td>
</tr>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PaymentReceivableUnderLicenseAgreement">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of payments expected to be received under the license agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentReceivableUnderLicenseAgreement</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
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<td>instant</td>
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</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of the payment receivable under the license agreement to be received on the earlier of approval by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PaymentReceivableUnderLicenseAgreementToBePaidAfterApproval</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_PeriodBeforeCollaborationPartnerPaysRoyaltiesOnNetSalesOfProductAfterFirstCommercialSaleInBrazil">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Period of time before collaboration partner pays royalties on net sales of product after first commercial sale in Brazil, in 'PnYnMnDTnHnMnS' format, for example, 'P1Y5M13D' represents the reported fact of one year, five months, and thirteen days.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_PeriodBeforeCollaborationPartnerPaysRoyaltiesOnNetSalesOfProductAfterFirstCommercialSaleInBrazil</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_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The number of separate performance obligations under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueFromContractWithCustomerNumberOfSeparatePerformanceObligations</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The minimum amount of revenue recognized in Latin America by the collaboration partner before paying royalties.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RevenueRecognizedByCollaborationPartnerInLatinAmericaBeforePayingRoyalties</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_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Royalty percentage received on the net sales of each drug in Latin America from the collaboration partner under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_RoyaltyPercentageReceivedOnNetSalesOfEachDrugInLatinAmericaFromCollaborationPartner</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>num:percentItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ContractWithCustomerLiability">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of obligation to transfer good or service to customer for which consideration has been received or is receivable.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130531-203044<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=82913815&amp;loc=SL49130532-203044<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130549-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>instant</td>
</tr>
</table></div>
</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ProceedsFromLicenseFeesReceived">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Cash received from licensees for license fees during the current period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 25<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3536-108585<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProceedsFromLicenseFeesReceived</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>debit</td>
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<tr>
<td><strong> Period Type:</strong></td>
<td>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_RevenueFromContractWithCustomerExcludingAssessedTax">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>
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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_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2018WithPTCTherapeuticsMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=ions_SublicenseRevenueMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_SublicenseRevenueMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
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<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ConsolidatedEntitiesAxis=ions_AkceaTherapeuticsIncMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ProductOrServiceAxis=us-gaap_LicenseMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=us-gaap_LicenseMember</td>
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<td>na</td>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6803043872">
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<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Collaborative Arrangements and Licensing Agreements, External Project Funding (Details)<br> $ in Millions</strong></div></th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
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<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones', window );">Maximum amount of payments payable for regulatory and commercialization milestones</a></td>
<td class="nump">$ 18<span></span>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_CollaborativeArrangementAndLicensingAgreementAbstract</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The maximum amount of payments payable for regulatory and commercialization milestones under the collaboration agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_MaximumAmountOfPaymentsPayableForRegulatoryAndCommercializationMilestones</td>
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<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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<td style="white-space:nowrap;">us-gaap_TypeOfArrangementAxis=ions_CollaborativeArrangementAndLicensingAgreementEnteredIntoInAugust2016WithCysticFibrosisFoundationMember</td>
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<td>na</td>
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<td><strong> Balance Type:</strong></td>
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<DOCUMENT>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6819558560">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Segment Information and Concentration of Business Risk, Segment Information (Details)<br> $ in Thousands</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
<th class="th" colspan="8">3 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
<th class="th" colspan="1"></th>
</tr>
<tr>
<th class="th">
<div>May 31, 2015 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Sep. 30, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Jun. 30, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Mar. 31, 2018 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Sep. 30, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Jun. 30, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Mar. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2018 </div>
<div>USD ($) </div>
<div>Segment</div>
</th>
<th class="th">
<div>Dec. 31, 2017 </div>
<div>USD ($)</div>
</th>
<th class="th">
<div>Dec. 31, 2016 </div>
<div>USD ($)</div>
</th>
<th class="th"><div>Jul. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingAbstract', window );"><strong>Segment Information and Concentration of Business Risk [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NumberOfReportableSegments', window );">Number of reportable segments | Segment</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="nump">$ 91,200<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 599,674<span></span>
</td>
<td class="nump">$ 514,179<span></span>
</td>
<td class="nump">$ 372,776<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingExpenses', window );">Total operating expenses</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 181,331<span></span>
</td>
<td class="nump">$ 163,967<span></span>
</td>
<td class="nump">$ 168,028<span></span>
</td>
<td class="nump">$ 147,720<span></span>
</td>
<td class="nump">$ 173,992<span></span>
</td>
<td class="nump">$ 107,002<span></span>
</td>
<td class="nump">$ 105,823<span></span>
</td>
<td class="nump">$ 96,315<span></span>
</td>
<td class="nump">661,046<span></span>
</td>
<td class="nump">483,132<span></span>
</td>
<td class="nump">392,936<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">10,782<span></span>
</td>
<td class="num">$ (18,572)<span></span>
</td>
<td class="num">$ (50,281)<span></span>
</td>
<td class="num">$ (3,301)<span></span>
</td>
<td class="num">(6,200)<span></span>
</td>
<td class="nump">$ 11,312<span></span>
</td>
<td class="nump">$ 6,450<span></span>
</td>
<td class="nump">$ 19,485<span></span>
</td>
<td class="num">(61,372)<span></span>
</td>
<td class="nump">31,047<span></span>
</td>
<td class="num">(20,160)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Assets', window );">Total assets as of current period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2,667,784<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,322,774<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,667,784<span></span>
</td>
<td class="nump">1,322,774<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_CommercialMember', window );">Commercial Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">254,922<span></span>
</td>
<td class="nump">120,014<span></span>
</td>
<td class="nump">22,767<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_SPINRAZARoyaltiesMember', window );">SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">237,930<span></span>
</td>
<td class="nump">112,540<span></span>
</td>
<td class="nump">883<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=us-gaap_ProductMember', window );">TEGSEDI Product Sales, Net [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,237<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember', window );">Licensing and Other Royalty Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">14,755<span></span>
</td>
<td class="nump">7,474<span></span>
</td>
<td class="nump">21,884<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember', window );">R&amp;D Revenue Under Collaborative Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 344,752<span></span>
</td>
<td class="nump">394,165<span></span>
</td>
<td class="nump">350,009<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NoncontrollingInterestAbstract', window );"><strong>Segment Information and Concentration of Business Risk [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_MinorityInterestOwnershipPercentageByParent', window );">Percentage ownership</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">75.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">68.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">75.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">68.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Ionis Core [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 641,944<span></span>
</td>
<td class="nump">525,185<span></span>
</td>
<td class="nump">385,424<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingExpenses', window );">Total operating expenses</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">380,212<span></span>
</td>
<td class="nump">373,788<span></span>
</td>
<td class="nump">322,192<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">261,732<span></span>
</td>
<td class="nump">151,397<span></span>
</td>
<td class="nump">63,232<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Assets', window );">Total assets as of current period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2,975,491<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,342,578<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,975,491<span></span>
</td>
<td class="nump">1,342,578<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Ionis Core [Member] | Commercial Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">240,685<span></span>
</td>
<td class="nump">120,014<span></span>
</td>
<td class="nump">22,767<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Ionis Core [Member] | SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">237,930<span></span>
</td>
<td class="nump">112,540<span></span>
</td>
<td class="nump">883<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Ionis Core [Member] | TEGSEDI Product Sales, Net [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Ionis Core [Member] | Licensing and Other Royalty Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
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<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,755<span></span>
</td>
<td class="nump">7,474<span></span>
</td>
<td class="nump">21,884<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Ionis Core [Member] | R&amp;D Revenue Under Collaborative Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">401,259<span></span>
</td>
<td class="nump">405,171<span></span>
</td>
<td class="nump">362,657<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Akcea Therapeutics [Member]</a></td>
<td class="text">&#160;<span></span>
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<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">64,867<span></span>
</td>
<td class="nump">43,401<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingExpenses', window );">Total operating expenses</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">295,683<span></span>
</td>
<td class="nump">163,871<span></span>
</td>
<td class="nump">83,512<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(230,816)<span></span>
</td>
<td class="num">(120,470)<span></span>
</td>
<td class="num">(83,512)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Assets', window );">Total assets as of current period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">365,261<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">268,804<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">365,261<span></span>
</td>
<td class="nump">268,804<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Akcea Therapeutics [Member] | Commercial Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">14,237<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Akcea Therapeutics [Member] | SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Akcea Therapeutics [Member] | TEGSEDI Product Sales, Net [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2,237<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Akcea Therapeutics [Member] | Licensing and Other Royalty Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">12,000<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember', window );">Operating Segments [Member] | Akcea Therapeutics [Member] | R&amp;D Revenue Under Collaborative Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">50,630<span></span>
</td>
<td class="nump">43,401<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_IntersegmentEliminationMember', window );">Elimination of Intercompany Activity [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(107,137)<span></span>
</td>
<td class="num">(54,407)<span></span>
</td>
<td class="num">(12,648)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingExpenses', window );">Total operating expenses</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(14,849)<span></span>
</td>
<td class="num">(54,527)<span></span>
</td>
<td class="num">(12,768)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(92,288)<span></span>
</td>
<td class="nump">120<span></span>
</td>
<td class="nump">120<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Assets', window );">Total assets as of current period</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (672,968)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (288,608)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(672,968)<span></span>
</td>
<td class="num">(288,608)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_IntersegmentEliminationMember', window );">Elimination of Intercompany Activity [Member] | Commercial Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_IntersegmentEliminationMember', window );">Elimination of Intercompany Activity [Member] | SPINRAZA Royalties [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_IntersegmentEliminationMember', window );">Elimination of Intercompany Activity [Member] | TEGSEDI Product Sales, Net [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_IntersegmentEliminationMember', window );">Elimination of Intercompany Activity [Member] | Licensing and Other Royalty Revenue [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="nump">0<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_ConsolidationItemsAxis=us-gaap_IntersegmentEliminationMember', window );">Elimination of Intercompany Activity [Member] | R&amp;D Revenue Under Collaborative Agreements [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract', window );"><strong>Segment Information [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax', window );">Revenue</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (107,137)<span></span>
</td>
<td class="num">$ (54,407)<span></span>
</td>
<td class="num">$ (12,648)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
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<div style="display: none;">
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>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>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 210<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-03(11))<br> -URI http://asc.fasb.org/extlink&amp;oid=6876686&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 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<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)(12))<br> -URI http://asc.fasb.org/extlink&amp;oid=6879938&amp;loc=d3e572229-122910<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_Assets</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The parent entity's interest in net assets of the subsidiary, expressed as a percentage.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_MinorityInterestOwnershipPercentageByParent</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NoncontrollingInterestAbstract</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of segments reported by the entity. A reportable segment is a component of an entity for which there is an accounting requirement to report separate financial information on that component in the entity's financial statements.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NumberOfReportableSegments</td>
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<td>us-gaap_</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Generally recurring costs associated with normal operations except for the portion of these expenses which can be clearly related to production and included in cost of sales or services. Includes selling, general and administrative expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingExpenses</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The net result for the period of deducting operating expenses from operating revenues.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingIncomeLoss</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130543-203045<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130539-203045<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 606<br> -SubTopic 10<br> -Section 50<br> -Paragraph 5<br> -URI http://asc.fasb.org/extlink&amp;oid=109196051&amp;loc=SL49130545-203045<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SegmentReportingAbstract</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SegmentReportingDisclosureOfEntitysReportableSegmentsAbstract</td>
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<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="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_CommercialMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
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<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_LicensingAndOtherRoyaltiesMember</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ProductOrServiceAxis=ions_ResearchAndDevelopmentRevenueUnderCollaborativeAgreementsMember</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ConsolidationItemsAxis=us-gaap_OperatingSegmentsMember</td>
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<td><strong> Data Type:</strong></td>
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</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_StatementBusinessSegmentsAxis=ions_IonisCoreMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementBusinessSegmentsAxis=ions_IonisCoreMember</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_StatementBusinessSegmentsAxis=ions_AkceaTherapeuticsMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_StatementBusinessSegmentsAxis=ions_AkceaTherapeuticsMember</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>
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</tr>
<tr>
<td><strong> Period Type:</strong></td>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_ConsolidationItemsAxis=us-gaap_IntersegmentEliminationMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_ConsolidationItemsAxis=us-gaap_IntersegmentEliminationMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
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<tr>
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<DOCUMENT>
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<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6797511472">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Segment Information and Concentration of Business Risk, Revenue from Significant Partners (Details) - Contracts Receivables [Member] - Credit Concentration [Member] - Significant Partners [Member] - Partner<br></strong></div></th>
<th class="th" colspan="2">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_SignificantPartnersAbstract', window );"><strong>Significant Partners [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConcentrationRiskPercentage1', window );">Concentration percentage</a></td>
<td class="nump">99.00%<span></span>
</td>
<td class="nump">84.00%<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_NumberOfSignificantPartners', window );">Number of significant partners</a></td>
<td class="nump">4<span></span>
</td>
<td class="nump">2<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_NumberOfSignificantPartners">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Represents the number of significant partners.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_NumberOfSignificantPartners</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<tr>
<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_ions_SignificantPartnersAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_SignificantPartnersAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
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<td><strong> Data Type:</strong></td>
<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
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<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskPercentage1">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>For an entity that discloses a concentration risk in relation to quantitative amount, which serves as the "benchmark" (or denominator) in the equation, this concept represents the concentration percentage derived from the division.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 18<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6351-108592<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 825<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13531-108611<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 21<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=109250915&amp;loc=d3e13537-108611<br><br>Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 275<br> -SubTopic 10<br> -Section 50<br> -Paragraph 20<br> -URI http://asc.fasb.org/extlink&amp;oid=99393423&amp;loc=d3e6404-108592<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskPercentage1</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
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<tr>
<td><strong> Data Type:</strong></td>
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<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByBenchmarkAxis=us-gaap_AccountsReceivableMember</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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<td><strong> Balance Type:</strong></td>
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<tr>
<td><strong> Period Type:</strong></td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CreditConcentrationRiskMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ConcentrationRiskByTypeAxis=us-gaap_CreditConcentrationRiskMember</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td></td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td></td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_srt_MajorCustomersAxis=ions_SignificantPartnersMember">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_MajorCustomersAxis=ions_SignificantPartnersMember</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>
<TYPE>XML
<SEQUENCE>114
<FILENAME>R82.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<body>
<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6797612560">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Employment Benefits (Details) - USD ($)<br></strong></div></th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_CompensationAndRetirementDisclosureAbstract', window );"><strong>Employment Benefits [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge', window );">Employee contribution limit per calendar year for employees under 50 years of age</a></td>
<td class="nump">$ 18,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge', window );">Employee contribution limit per calendar year for employees over 50 years of age</a></td>
<td class="nump">24,500<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DefinedContributionPlanCostRecognized', window );">Matching contributions</a></td>
<td class="nump">$ 5,700,000<span></span>
</td>
<td class="nump">$ 3,000,000<span></span>
</td>
<td class="nump">$ 1,700,000<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The limit of annual employee contributions to the plan per calendar year by eligible employees who are over 50 years of age.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsOverFiftyYearsAge</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>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The limit of annual employee contributions to the plan per calendar year by eligible employees who are under 50 years of age.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_DefinedContributionPlanEmployeeContributionLimitByPlanParticipantsUnderFiftyYearsAge</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_CompensationAndRetirementDisclosureAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_CompensationAndRetirementDisclosureAbstract</td>
</tr>
<tr>
<td style="padding-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>
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</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DefinedContributionPlanCostRecognized">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of cost for defined contribution plan.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 715<br> -SubTopic 70<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=49170846&amp;loc=d3e28014-114942<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_DefinedContributionPlanCostRecognized</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<DOCUMENT>
<TYPE>XML
<SEQUENCE>115
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<DESCRIPTION>IDEA: XBRL DOCUMENT
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<html>
<head>
<title></title>
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6804241616">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Legal Proceedings (Details) - Gilead Litigation [Member]<br> $ in Billions</strong></div></th>
<th class="th" colspan="1">1 Months Ended</th>
</tr>
<tr><th class="th">
<div>Mar. 31, 2016 </div>
<div>USD ($) </div>
<div>Claim </div>
<div>Defense</div>
</th></tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_LossContingencyAbstract', 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="top.Show.showAR( this, 'defref_us-gaap_LossContingencyPendingClaimsNumber', window );">Number of asserted claims | Claim</a></td>
<td class="nump">10<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward', window );">Percentage of entitled past sales of sofosbuvir included in award</a></td>
<td class="nump">4.00%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LossContingenciesPastSalesOfMedicationIncludedInAward', window );">Past sales of sofosbuvir included in award | $</a></td>
<td class="nump">$ 5<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_LossContingenciesNumberOfAdditionalNonJuryDefensesAsserted', window );">Number of additional non-jury defenses asserted | Defense</a></td>
<td class="nump">2<span></span>
</td>
</tr>
</table>
<div style="display: none;">
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ions_LossContingenciesNumberOfAdditionalNonJuryDefensesAsserted">
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of additional non-jury defenses asserted in the suit.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LossContingenciesNumberOfAdditionalNonJuryDefensesAsserted</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Past sales of sofosbuvir, a medication used for the treatment of hepatitis C, used in calculation of award to Merck Sharp &amp; Dohme Corp. and the Company by the jury.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LossContingenciesPastSalesOfMedicationIncludedInAward</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
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<td>credit</td>
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<td>duration</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage applied to past sales of sofosbuvir, a medication used for the treatment of hepatitis C, used in the calculation of award to Merck Sharp &amp; Dohme Corp. and the Company by the jury.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_LossContingenciesPercentageAppliedToPastSalesOfMedicationIncludedInAward</td>
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<td>ions_</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LossContingencyAbstract">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LossContingencyAbstract</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td>xbrli:stringItemType</td>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_LossContingencyPendingClaimsNumber">
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of pending claims pertaining to a loss contingency.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 450<br> -SubTopic 20<br> -Section 50<br> -Paragraph 4<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=82911808&amp;loc=d3e14435-108349<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_LossContingencyPendingClaimsNumber</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>xbrli:integerItemType</td>
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<td>na</td>
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<td>instant</td>
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<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Details</a><div><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">srt_LitigationCaseAxis=ions_SuitRelatedToUSPatentsMember</td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
<td>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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<DOCUMENT>
<TYPE>XML
<SEQUENCE>116
<FILENAME>R84.htm
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
<html>
<head>
<title></title>
<link rel="stylesheet" type="text/css" href="report.css">
<script type="text/javascript" src="Show.js">/* Do Not Remove This Comment */</script><script type="text/javascript">
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<span style="display: none;">v3.10.0.1</span><table class="report" border="0" cellspacing="2" id="idp6804152656">
<tr>
<th class="tl" colspan="1" rowspan="2"><div style="width: 200px;"><strong>Quarterly Financial Data (Unaudited) (Details) - USD ($)<br> $ / shares in Units, shares in Thousands, $ in Thousands</strong></div></th>
<th class="th" colspan="16">3 Months Ended</th>
<th class="th" colspan="1">6 Months Ended</th>
<th class="th" colspan="3">12 Months Ended</th>
</tr>
<tr>
<th class="th" colspan="2"><div>Dec. 31, 2018</div></th>
<th class="th" colspan="2"><div>Sep. 30, 2018</div></th>
<th class="th" colspan="2"><div>Jun. 30, 2018</div></th>
<th class="th" colspan="2"><div>Mar. 31, 2018</div></th>
<th class="th" colspan="2"><div>Dec. 31, 2017</div></th>
<th class="th" colspan="2"><div>Sep. 30, 2017</div></th>
<th class="th" colspan="2"><div>Jun. 30, 2017</div></th>
<th class="th" colspan="2"><div>Mar. 31, 2017</div></th>
<th class="th"><div>Jun. 30, 2017</div></th>
<th class="th"><div>Dec. 31, 2018</div></th>
<th class="th"><div>Dec. 31, 2017</div></th>
<th class="th"><div>Dec. 31, 2016</div></th>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Quarterly Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_Revenues', window );">Revenue</a></td>
<td class="nump">$ 192,113<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 145,395<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 117,747<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 144,419<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 167,792<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 118,314<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 112,273<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 115,800<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingExpenses', window );">Operating expenses</a></td>
<td class="nump">181,331<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">163,967<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">168,028<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">147,720<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">173,992<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">107,002<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">105,823<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">96,315<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 661,046<span></span>
</td>
<td class="nump">$ 483,132<span></span>
</td>
<td class="nump">$ 392,936<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_OperatingIncomeLoss', window );">Income (loss) from operations</a></td>
<td class="nump">10,782<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(18,572)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(50,281)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(3,301)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(6,200)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">11,312<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">6,450<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">19,485<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(61,372)<span></span>
</td>
<td class="nump">31,047<span></span>
</td>
<td class="num">(20,160)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ProfitLoss', window );">Net income (loss)</a></td>
<td class="nump">302,735<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(20,365)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(56,573)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(10,812)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(9,169)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(7,493)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(3,085)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">8,964<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">214,985<span></span>
</td>
<td class="num">(10,783)<span></span>
</td>
<td class="num">(60,400)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="nump">$ 320,078<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (4,559)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (40,358)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (1,420)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (2,922)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (2,611)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (3,085)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 8,964<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 273,741<span></span>
</td>
<td class="nump">$ 346<span></span>
</td>
<td class="num">$ (60,400)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="nump">$ 2.32<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.03)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.29)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.01)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.03)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2]</sup></td>
<td class="num">$ (0.02)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[1],[2],[3]</sup></td>
<td class="num">$ (0.02)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">$ 0.07<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2.09<span></span>
</td>
<td class="nump">$ 0.15<span></span>
</td>
<td class="num">$ (0.50)<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareDiluted', window );">Diluted net income (loss) per share (in dollars per share)</a></td>
<td class="nump">$ 2.21<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2],[4]</sup></td>
<td class="num">$ (0.03)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="num">$ (0.29)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="num">$ (0.01)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="num">$ (0.03)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="num">$ (0.02)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2],[3]</sup></td>
<td class="num">$ (0.02)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2]</sup></td>
<td class="nump">$ 0.07<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"><sup>[2],[5],[6]</sup></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 2.07<span></span>
</td>
<td class="nump">$ 0.15<span></span>
</td>
<td class="num">$ (0.50)<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract', window );"><strong>Income (Numerator) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic', window );">Income (loss) available to Ionis common stockholders</a></td>
<td class="nump">$ 319,694<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (4,563)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (37,932)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (1,212)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (3,124)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (1,976)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 8,964<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 276,868<span></span>
</td>
<td class="nump">$ 18,792<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DilutiveSecuritiesEffectOnBasicEarningsPerShareOther', window );">Shares issuable related to our 1% convertible notes</a></td>
<td class="nump">10,745<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted', window );">Income available to Ionis common shareholders, plus assumed conversions</a></td>
<td class="nump">$ 330,439<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 8,964<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 276,868<span></span>
</td>
<td class="nump">$ 18,792<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfSharesOutstandingDilutedDisclosureItemsAbstract', window );"><strong>Shares (Denominator) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic', window );">Shares used in computing basic net income (loss) per share (in shares)</a></td>
<td class="nump">137,699<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">137,346<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">128,712<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">125,330<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">124,818<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">124,370<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">122,861<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">132,320<span></span>
</td>
<td class="nump">124,016<span></span>
</td>
<td class="nump">120,933<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_IncrementalCommonSharesAttributableToDilutiveEffectOfEmployeeStockPurchasePlan', window );">Shares issuable related to our ESPP (in shares)</a></td>
<td class="nump">7<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">60<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities', window );">Shares issuable related to our 1% convertible notes (in shares)</a></td>
<td class="nump">10,260<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rou">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding', window );">Shares used in computing diluted net income per share (in shares)</a></td>
<td class="nump">149,856<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">124,972<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">134,056<span></span>
</td>
<td class="nump">126,098<span></span>
</td>
<td class="nump">120,933<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes1PercentMember', window );">1 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Quarterly Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
<td class="nump">1.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentAxis=ions_ConvertibleSeniorNotes275PercentMember', window );">2 3/4 Percent Convertible Senior Notes [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Quarterly Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_DebtInstrumentInterestRateStatedPercentage', window );">Interest rate on convertible senior notes</a></td>
<td class="nump">2.75%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">2.75%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">2.75%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
<td class="nump">2.75%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_EmployeeStockOptionMember', window );">Stock Options [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements', window );">Shares issuable related to stock-based compensation (in shares)</a></td>
<td class="nump">1,254<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">1,674<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">1,216<span></span>
</td>
<td class="nump">1,619<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_AwardTypeAxis=us-gaap_RestrictedStockMember', window );">Restricted Stock Awards [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract', window );"><strong>Effect of Diluted Securities [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements', window );">Shares issuable related to stock-based compensation (in shares)</a></td>
<td class="nump">636<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">377<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">514<span></span>
</td>
<td class="nump">459<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_StatementBusinessSegmentsAxis=ions_IonisCoreMember', window );">Ionis [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Quarterly Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="nump">$ 372,913<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 43,226<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 5,882<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 18,785<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 10,510<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">$ 10,144<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">$ 440,806<span></span>
</td>
<td class="nump">$ 110,776<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Quarterly Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="num">(53,219)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(47,789)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(43,814)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(19,997)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(13,634)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">(12,120)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">(163,938)<span></span>
</td>
<td class="num">(91,984)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SaleOfStockPercentageOfOwnershipBeforeTransaction', window );">Percentage ownership</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">100.00%<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">100.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">100.00%<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Common Stock [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Quarterly Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="num">$ (53,219)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (47,789)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (43,814)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (19,997)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (13,634)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (12,063)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (163,938)<span></span>
</td>
<td class="num">$ (63,638)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="num">$ (0.79)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.73)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.72)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.44)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.30)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.33)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (2.74)<span></span>
</td>
<td class="num">$ (3.08)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_WeightedAverageNumberOfSharesOwnedInSubsidiary', window );">Weighted average shares owned in Akcea (in shares)</a></td>
<td class="nump">67,130<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">65,538<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">60,832<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">45,448<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">45,448<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">36,556<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">59,812<span></span>
</td>
<td class="nump">20,669<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="rh">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_srt_OwnershipAxis=ions_AkceaTherapeuticsIncMember', window );">Akcea [Member] | Preferred Stock [Member]</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_SelectedQuarterlyFinancialInformationAbstract', window );"><strong>Quarterly Financial Data (Unaudited) [Abstract]</strong></a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_NetIncomeLoss', window );">Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (57)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (28,346)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_EarningsPerShareBasic', window );">Basic net income (loss) per share (in dollars per share)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="num">$ (0.01)<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="num">$ (1.80)<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_PreferredStockDividendRatePercentage', window );">Dividend rate</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">6.00%<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl " style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_us-gaap_ConvertiblePreferredStockTermsOfConversion', window );">Conversion ratio</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">converted into common stock on a 1:1 basis<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr class="re">
<td class="pl custom" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="top.Show.showAR( this, 'defref_ions_WeightedAverageNumberOfSharesOwnedInSubsidiary', window );">Weighted average shares owned in Akcea (in shares)</a></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="nump">5,651<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="fn" style="border-bottom: 0px;"></td>
<td class="text">&#160;<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
<td class="nump">15,748<span></span>
</td>
<td class="text">&#160;<span></span>
</td>
</tr>
<tr><td colspan="21"></td></tr>
<tr><td colspan="21"><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">As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income (loss) per share calculation for each of the quarters in 2018 and for the third and fourth quarters of 2017 considered our net income for Ionis on a stand-alone basis plus our share of Akcea's net loss for the period. To calculate the portion of Akcea's net loss attributable to our ownership, we multiplied Akcea's loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[2]</td>
<td style="vertical-align: top;" valign="top">We computed net income (loss) per share independently for each of the quarters presented. Therefore, the sum of the quarterly net income (loss) per share will not necessarily equal the total for the year.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[3]</td>
<td style="vertical-align: top;" valign="top">Prior to Akcea's IPO in July 2017, we owned Akcea series A convertible preferred stock, which included a six percent cumulative dividend. Upon completion of Akcea's IPO in July 2017, our preferred stock was converted into common stock on a 1:1 basis. The preferred stock dividend was not paid at the IPO because the IPO was not a liquidation event or a change in control. During the three months ended September 30, 2017, Akcea used a two-class method to compute its net income (loss) per share because it had both common and preferred shares outstanding during the periods. The two-class method required Akcea to calculate its net income (loss) per share for each class of stock by dividing total distributable losses applicable to preferred and common stock, including the six percent cumulative dividend contractually due to series A convertible preferred shareholders, by the weighted-average of preferred and common shares outstanding during the requisite period. Since Akcea used the two-class method, accounting rules required us to include our portion of Akcea's net income (loss) per share for both Akcea's common and preferred shares that we owned in our calculation of basic and diluted net income (loss) per share for the three months ended September 30, 2017.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[4]</td>
<td style="vertical-align: top;" valign="top">For the three months ended December 31, 2018, we had net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[5]</td>
<td style="vertical-align: top;" valign="top">For the three months ended March 31, 2017, the calculation excluded the 1 percent and 2.75 percent notes because the effect on diluted earnings per share was anti-dilutive.</td>
</tr>
<tr class="outerFootnote">
<td style="vertical-align: top; width: 12pt;" valign="top">[6]</td>
<td style="vertical-align: top;" valign="top">For the three months ended March 31, 2017, we owned 100 percent of Akcea. As a result, we did not have to adjust our earnings per share calculation. For the three months ended March 31, 2017, we had net income. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during those periods.</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_IncrementalCommonSharesAttributableToDilutiveEffectOfEmployeeStockPurchasePlan">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of shares issuable under the Company's employee stock purchase plan (ESPP).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_IncrementalCommonSharesAttributableToDilutiveEffectOfEmployeeStockPurchasePlan</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_WeightedAverageNumberOfSharesOwnedInSubsidiary">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of shares owned in the subsidiary during the reporting period determined by relating the portion of time within a reporting period that shares have been owned to the total time in that period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ions_WeightedAverageNumberOfSharesOwnedInSubsidiary</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ions_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_ConvertiblePreferredStockTermsOfConversion">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Specific terms relevant to convertibility. Includes class of preferred stock and number of shares convertible into, exercise (or conversion) price or rates, dates relevant to conversion timing and events relevant to conversion. Describe also any beneficial conversion features. where convertible preferred stock with a nondetachable conversion feature is in-the-money at commitment date. For contingently convertible preferred stock, discuss the circumstances of the contingency, including the events or changes in circumstance that would cause the contingency to be met and any of the significant features necessary to understand the conversion rights and the timing of those rights. Include also an events or changes in circumstance, if any, that could adjust or change the contingency, conversion price, or number of shares, including significant terms of those changes.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 8<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21538-112644<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(28))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 3: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21521-112644<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(27))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br><br>Reference 5: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 6<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21506-112644<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 505<br> -SubTopic 10<br> -Section 50<br> -Paragraph 3<br> -URI http://asc.fasb.org/extlink&amp;oid=109259400&amp;loc=d3e21475-112644<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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</tr>
<tr>
<td><strong> 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_DebtInstrumentInterestRateStatedPercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Contractual interest rate for funds borrowed, under the debt agreement.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 210<br> -SubTopic 10<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.5-02.22(a)(1))<br> -URI http://asc.fasb.org/extlink&amp;oid=6877327&amp;loc=d3e13212-122682<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<tr>
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</div></td></tr>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_DilutiveSecuritiesEffectOnBasicEarningsPerShareOther">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of increase (decrease) to net income used for calculating diluted earnings per share (EPS), resulting from the assumed exercise of dilutive convertible securities excluding adjustments related to ESOP convertible preferred stock, stock options, and restrictive stock units.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
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<td><strong> Data Type:</strong></td>
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</tr>
<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_EarningsPerShareBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period per each share of common stock or unit outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(19))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&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 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1337-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=109256448&amp;loc=d3e4984-109258<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 (SX 210.5-03(21))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<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> -URI http://asc.fasb.org/extlink&amp;oid=109234566&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 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1252-109256<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 942<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&amp;loc=SL114874048-224260<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=SL5780133-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>num:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_EarningsPerShareDiluted">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The amount of net income (loss) for the period available to each share of common stock or common unit outstanding during the reporting period and to each share or unit that would have been outstanding assuming the issuance of common shares or units for all dilutive potential common shares or units outstanding during the reporting period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 55<br> -Paragraph 52<br> -URI http://asc.fasb.org/extlink&amp;oid=109256448&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 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1252-109256<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<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(23))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&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 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109234566&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 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 7<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1337-109256<br><br>Reference 7: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(21))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br><br>Reference 8: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 60B<br> -Subparagraph (d)<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&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 944<br> -SubTopic 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(19))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&amp;loc=SL114874131-224263<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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>num:perShareItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of convertible debt securities using the if-converted method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 40<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1930-109256<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncrementalCommonSharesAttributableToConversionOfDebtSecurities</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Additional shares included in the calculation of diluted EPS as a result of the potentially dilutive effect of share based payment arrangements using the treasury stock method.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28A<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1500-109256<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_IncrementalCommonSharesAttributableToShareBasedPaymentArrangements</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:sharesItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The portion of profit or loss for the period, net of income taxes, which is attributable to the parent.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<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 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.9-04(22))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873765&amp;loc=SL114874048-224260<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<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 220<br> -Section S99<br> -Paragraph 1<br> -Subparagraph (SX 210.7-04(18))<br> -URI http://asc.fasb.org/extlink&amp;oid=114873790&amp;loc=SL114874131-224263<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 S99<br> -Paragraph 2<br> -Subparagraph (SX 210.5-03(20))<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&amp;loc=SL114868664-224227<br><br>Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 230<br> -SubTopic 10<br> -Section 45<br> -Paragraph 28<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3602-108585<br><br>Reference 7: 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> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_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_NetIncomeLossAvailableToCommonStockholdersBasic">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after deduction of tax, noncontrolling interests, dividends on preferred stock and participating securities; of income (loss) available to common shareholders.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 250<br> -SubTopic 10<br> -Section 50<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109234566&amp;loc=d3e22694-107794<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 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1377-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount, after deduction of tax, noncontrolling interests, dividends on preferred stock and participating securities, and addition from assumption of issuance of common shares for dilutive potential common shares; of income (loss) available to common shareholders.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1505-109256<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 45<br> -Paragraph 11<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1377-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAvailableToCommonStockholdersDiluted</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
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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_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_NetIncomeLossAvailableToCommonStockholdersDilutedAbstract</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</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_OperatingExpenses">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Generally recurring costs associated with normal operations except for the portion of these expenses which can be clearly related to production and included in cost of sales or services. Includes selling, general and administrative expense.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_OperatingExpenses</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_OperatingIncomeLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The net result for the period of deducting operating expenses from operating revenues.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><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_PreferredStockDividendRatePercentage">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The percentage rate used to calculate dividend payments on preferred stock.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_PreferredStockDividendRatePercentage</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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_ProfitLoss">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1A<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669619-108580<br><br>Reference 2: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (a)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 3: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 220<br> -SubTopic 10<br> -Section 45<br> -Paragraph 1B<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=114867106&amp;loc=SL7669625-108580<br><br>Reference 4: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1A<br> -Subparagraph (c)(1)<br> -URI http://asc.fasb.org/extlink&amp;oid=109239629&amp;loc=SL4573702-111684<br><br>Reference 5: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<br><br>Reference 6: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4J<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591551-111686<br><br>Reference 7: 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 2<br> -URI http://asc.fasb.org/extlink&amp;oid=109223946&amp;loc=d3e3000-108585<br><br>Reference 8: 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 19<br> -URI http://asc.fasb.org/extlink&amp;oid=108774443&amp;loc=SL4569616-111683<br><br>Reference 9: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (c)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8933-108599<br><br>Reference 10: http://www.xbrl.org/2003/role/exampleRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 810<br> -SubTopic 10<br> -Section 55<br> -Paragraph 4K<br> -URI http://asc.fasb.org/extlink&amp;oid=84234705&amp;loc=SL4591552-111686<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_ProfitLoss</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>xbrli:monetaryItemType</td>
</tr>
<tr>
<td><strong> Balance Type:</strong></td>
<td>credit</td>
</tr>
<tr>
<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
</table></div>
</div></td></tr>
</table>
<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_us-gaap_Revenues">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Amount of revenue recognized from goods sold, services rendered, insurance premiums, or other activities that constitute an earning process. Includes, but is not limited to, investment and interest income before deduction of interest expense when recognized as a component of revenue, and sales and trading gain (loss).</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/disclosureRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 22<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<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 210.5-03.1)<br> -URI http://asc.fasb.org/extlink&amp;oid=115205541&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 280<br> -SubTopic 10<br> -Section 50<br> -Paragraph 32<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&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 22<br> -Subparagraph (b)<br> -URI http://asc.fasb.org/extlink&amp;oid=115929826&amp;loc=d3e8736-108599<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_Revenues</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>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_SaleOfStockPercentageOfOwnershipBeforeTransaction">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Percentage of subsidiary's or equity investee's stock owned by parent company before stock transaction.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SaleOfStockPercentageOfOwnershipBeforeTransaction</td>
</tr>
<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>us-gaap_</td>
</tr>
<tr>
<td><strong> Data Type:</strong></td>
<td>num: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_SelectedQuarterlyFinancialInformationAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_SelectedQuarterlyFinancialInformationAbstract</td>
</tr>
<tr>
<td style="padding-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_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustmentAbstract</td>
</tr>
<tr>
<td style="padding-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_WeightedAverageNumberOfDilutedSharesOutstanding">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="top.Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>The average number of shares or units issued and outstanding that are used in calculating diluted EPS or earnings per unit (EPU), determined based on the timing of issuance of shares or units in the period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&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 45<br> -Paragraph 16<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1505-109256<br></p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- Definition</a><div><p>Number of [basic] shares or units, after adjustment for contingently issuable shares or units and other shares or units not deemed outstanding, determined by relating the portion of time within a reporting period that common shares or units have been outstanding to the total time in that period.</p></div>
<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 45<br> -Paragraph 10<br> -URI http://asc.fasb.org/extlink&amp;oid=109260490&amp;loc=d3e1448-109256<br><br>Reference 2: http://fasb.org/us-gaap/role/ref/legacyRef<br> -Publisher FASB<br> -Name Accounting Standards Codification<br> -Topic 260<br> -SubTopic 10<br> -Section 50<br> -Paragraph 1<br> -Subparagraph (a)<br> -URI http://asc.fasb.org/extlink&amp;oid=6371337&amp;loc=d3e3550-109257<br></p></div>
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<a href="javascript:void(0);" onclick="top.Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
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end
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>XML
<SEQUENCE>118
<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>119
<FILENAME>report.css
<DESCRIPTION>IDEA: XBRL DOCUMENT
<TEXT>
/* Updated 2009-11-04 */
/* v2.2.0.24 */

/* DefRef Styles */
..report table.authRefData{
	background-color: #def;
	border: 2px solid #2F4497;
	font-size: 1em;
	position: absolute;
}

..report table.authRefData a {
	display: block;
	font-weight: bold;
}

..report table.authRefData p {
	margin-top: 0px;
}

..report table.authRefData .hide {
	background-color: #2F4497;
	padding: 1px 3px 0px 0px;
	text-align: right;
}

..report table.authRefData .hide a:hover {
	background-color: #2F4497;
}

..report table.authRefData .body {
	height: 150px;
	overflow: auto;
	width: 400px;
}

..report table.authRefData table{
	font-size: 1em;
}

/* Report Styles */
..pl a, .pl a:visited {
	color: black;
	text-decoration: none;
}

/* table */
..report {
	background-color: white;
	border: 2px solid #acf;
	clear: both;
	color: black;
	font: normal 8pt Helvetica, Arial, san-serif;
	margin-bottom: 2em;
}

..report hr {
	border: 1px solid #acf;
}

/* Top labels */
..report th {
	background-color: #acf;
	color: black;
	font-weight: bold;
	text-align: center;
}

..report th.void	{
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	color: #000000;
	font: bold 10pt Helvetica, Arial, san-serif;
	text-align: left;
}

..report .pl {
	text-align: left;
	vertical-align: top;
	white-space: normal;
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}

..report td.pl a.a {
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	width: 200px;
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}

..report td.pl div.a {
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..report td.pl a:hover {
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}

/* Header rows... */
..report tr.rh {
	background-color: #acf;
	color: black;
	font-weight: bold;
}

/* Calendars... */
..report .rc {
	background-color: #f0f0f0;
}

/* Even rows... */
..report .re, .report .reu {
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}

..report .reu td {
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}

/* Odd rows... */
..report .ro, .report .rou {
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}

..report .rou td {
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}

..report .rou table td, .report .reu table td {
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}

/* styles for footnote marker */
..report .fn {
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}

/* styles for numeric types */
..report .num, .report .nump {
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	white-space: nowrap;
}

..report .nump {
	padding-left: 2em;
}

..report .nump {
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}

/* styles for text types */
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end
</TEXT>
</DOCUMENT>
</SEC-DOCUMENT>
